1. Introduction
Mortality from cancer is about to surpass that from cardiovascular diseases in near future. About 7 million people die from cancer-related cases per year, and it is estimated that there will be more than 16 million new cancer cases every year by 2020 [ 1 , 2 ]. Cancer is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues leading to the formation of tumor mass, vascularization, and metastasis (spread of cancer to other parts of the body) [ 3 ]. Though angiogenesis (growth of new blood vessels from preexisting vessels) is a normal and vital process in growth and development, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one [ 4 ]. Chemotherapy is one of the major approaches to treat cancer by delivering a cytotoxic agent to the cancer cells. The main problem with the conventional chemotherapy is the inability to deliver the correct amount of drug directly to cancer cells without affecting normal cells [ 5 ]. Drug resistance, altered biodistribution, biotransformation, and drug clearance are also common problems [ 5 ]. Targeted chemotherapy and drug delivery techniques are emerging as a powerful method to circumvent such problems [ 6 – 10 ]. This will allow the selective and effective localization of drugs at predefined targets (e.g., overexpressed receptors in cancer) while restricting its access to normal cell thus maximizing therapeutic index and reducing toxicity.
Discovery of several protein/peptide receptors and tumor-related peptides and proteins is expected to create a “new wave” of more effective and selective anticancer drugs in the future, capturing the large share of the cancer therapeutic market [ 6 , 8 , 11 ]. The “biologics” treatment option against cancer includes the use of proteins, monoclonal antibodies, and peptides. The monoclonal antibodies (mAbs) and large protein ligands have two major limitations compared to peptides: poor delivery to tumors due to their large size and dose-limiting toxicity to the liver and bone marrow due to nonspecific uptake into the reticuloendothelial system. The use of such macromolecules has therefore been restricted to either vascular targets present on the luminal side of tumor vessel endothelium or hematological malignancies [ 12 – 17 ]. Peptides possess many advantages, such as small size, ease of synthesis and modification, tumor-penetrating ability, and good biocompatibility [ 18 , 19 ]. Peptide degradation by proteolysis can be prevented by chemical modifications such as incorporation of D-amino acids or cyclization [ 18 ].
Over the years peptides have been evolved as promising therapeutic agents in the treatment of cancer, diabetes, and cardiovascular diseases, and application of peptides in a variety of other therapeutic areas is growing rapidly. Currently there are about 60 approved peptide drugs in the market generating an annual sale of more than $13 billion [ 18 ]. Out of four peptide drugs in the market which have reached global sales over $1 billion, three peptides are used in treating cancer directly or in the treatment of episodes associated with certain tumors (leuprolide, goserelin, and octreotide). The number of peptide drugs entering clinical trials is increasing steadily; it was 1.2 per year in the 1970s, 4.6 per year in the 1980s, 9.7 per year in the 1990s, and 16.8 per in 2000s [ 19 ]. There are several hundred peptide candidates in the clinic and preclinic development. From 2000 onwards, peptides entering clinical study were most frequently for indications of cancer (18%) and metabolic disorders (17%) [ 20 ].
This paper focuses on different strategies of employing peptides in cancer treatment and management. A special emphasis is given to current peptide drugs available in the market for treating cancer and also peptide candidates in clinical and preclinical stages of development. Peptides can be utilized in a number of different ways in treating cancer [ 8 – 10 , 19 ]. This includes using peptides directly as drugs (e.g., as angiogenesis inhibitors), tumor targeting agents that carry cytotoxic drugs and radionuclides (targeted chemotherapy and radiation therapy), hormones, and vaccines. Different possible cancer treatment options using peptides are summarized in Figure 1 . Due to the ability to bind to different receptors and also being part of several biochemical pathways, peptides act as potential diagnostic tool and biomarkers in cancer progression. Out of these different possibilities, peptide drugs currently available in the market come from peptide hormone therapy and tumor targeting agents carrying radionuclides (peptide-receptor radio nuclide therapy and imaging). Exceptions to these are two short chain peptide-related drugs, bortezomib and mifamurtide [ 21 , 22 ]. There is a tremendous progress in other areas such as peptide-vaccine development and peptide angiogenesis inhibitors, and several clinical trials are underway which is expected to bear fruit in near future providing better options to millions of cancer patients.
2. Peptide Hormones: LHRH Agonists and Antagonists
The best classical example of the application of peptides in cancer treatment is the use of LHRH (luteinizing hormone-releasing hormone) agonists introduced by Schally et al. as a therapy for prostate cancer [ 23 – 25 ]. Since then, depot formulations of LHRH agonists such as buserelin, leuprolide, goserelin, and triptorelin have been developed for more efficacious and more convenient treatment of patients with prostate cancer [ 26 – 28 ]. Administration of these peptides causes downregulation of LHRH receptors in the pituitary, leading to an inhibition of follicle-stimulating hormone (FSH) and LH release, and a concomitant decrease in testosterone production. This offered a new method for androgen deprivation therapy in prostate cancer patients. Discovery of LHRH antagonists resulted in therapeutic improvement over agonists as they cause an immediate and dose-related inhibition of LH and FSH by competitive blockade of the LHRH receptors. To date, many potent LHRH antagonists are available for the clinical use in patients. Cetrorelix was the first LHRH antagonist given marketing approval and, thus, became the first LHRH antagonist available clinically [ 29 ]. Subsequently new generation LHRH antagonists such as abarelix and degarelix have been approved for human use [ 30 , 31 ]. A list of LHRH agonists and antagonists available in the market is shown in Table 1 .
3. Peptide as Radionuclide Carrier: Somatostatin Analogues in Cancer Therapy and Peptide Receptor Radionuclide Therapy (PRRT)
Apart from the use of peptide-based LHRH agonists and antagonists for treating cancer, somatostatin analogues are the only approved cancer therapeutic peptides in the market [ 32 ]. Potent analogues of somatostatin (peptide hormone consisting of 14 amino acids, found in δ cells of the pancreas as well as in hypothalamic and other gastrointestinal cells) including octreotide (sandostatin) have been developed for the treatment of acromegaly, gigantism, thyrotropinoma, diarrhea and flushing episodes associated with carcinoid syndrome, and diarrhea in patients with vasoactive intestinal peptide-secreting tumors (VIPomas) [ 33 ]. Similarly, another long-acting analogue of somatostatin, lanreotide (somatuline), is used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome and VIPomas [ 34 ].
Most neuroendocrine tumors (NETs) feature a strong overexpression of somatostatin receptors, mainly of subtype 2 (sst2). Currently five somatostatin receptor subtypes (sst) are known (sst1-5) [ 32 , 35 ]. The density of these receptors is vastly higher than on nontumor tissues. Therefore, somatostatin receptors are attractive targets for delivery of radioactivity via radiolabeled somatostatin analogs. The sst2 has been shown to internalize into the cell in a fast, efficient, and reversible manner after specific binding of a receptor agonist. This molecular process is likely to be responsible for the high and long-lasting uptake of radioactivity in the target cell after binding of the radiolabeled somatostatin analog. Introduced in the late 1980s, [111In-DTPA]-octreotide (Octreoscan), the first available radiolabeled somatostatin analog, rapidly became the gold standard for diagnosis of sst-positive NETs [ 36 , 37 ]. Numerous peptide-based tracers targeting somatostatin receptors have been developed over the past decade [ 36 , 37 ]. Octreoscan and NeoTect (tc-99m depreotide) are the only radiopeptide tracers on the market approved by the Food and Drug Administration [ 37 , 38 ]. An octreotide scan or octreoscan is a type of scintigraphy used to find carcinoid and other types of tumors and to localize sarcoidosis. Octreotide, a drug similar to somatostatin, is radiolabeled with indium-111 and is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide and makes pictures showing where the tumor cells are in the body. NeoTect is a radioactive imaging test used to evaluate certain lung lesions in patients who test positive for lung lesions using other imaging tests (e.g., CT or MRI) and have been diagnosed with cancer or have a strong likelihood of cancer. NeoTect identifies certain cells that may be associated with lung cancer and sometimes with other conditions [ 38 ].
Peptide receptor radionuclide therapy (PRRT) combines octreotide (or other somatostatin analogs) with a radionuclide (a radioactive substance) to form highly specialized molecules called radiolabeled somatostatin analogues or radiopeptides [ 39 – 48 ]. Radiolabeled somatostatin analogs generally comprise three main parts: a cyclic octapeptide (e.g., octreotide), a chelator (e.g., DTPA or DOTA), and a radioactive element (111In, 90Y, or 177Lu). These radiopeptides can be injected into a patient and will travel throughout the body binding to carcinoid tumor cells that have receptors for them. Once bound, these radiopeptides emit radiation and kill the tumor cells they are bound to ( Figure 2 ). PRRT using [111In-DTPA]-octreotide (where DTPA is diethylenetriamine pentaacetic acid) is feasible because, besides gamma radiation, 111In emits both therapeutic Auger and internal conversion electrons having tissue penetration ability [ 39 , 40 ]. However, studies have shown that 111In-coupled peptides are not efficient for PRRT, as the short distance traveled by Auger electrons after emission means that decay of 111In has to occur close to the cell nucleus to be tumoricidal [ 39 , 40 ]. It was found that replacement of phenylalanine by tyrosine as the third amino acid in the octapeptide leads to an increased affinity for somatostatin-receptor subtype 2. This resulted in the development of next generation therapy using 90Y-DOTA, Tyr3-octreotide [ 41 – 44 ]. This compound has DOTA (tetraazacyclododecane tetraacetic acid) instead of DTPA as the chelator, which allows stable binding of 90Y, a β -emitting radionuclide. Various clinical trials around the world showed that it is better than [111In-DTPA]-octreotide in treating gastroenteropancreatic neuroendocrine tumors (GEPNETs). A third generation of somatostatin-receptor-targeted radionuclide therapies was introduced using 177Lu-DOTA, Tyr3-octreotate [ 49 , 50 ]. The only difference between DOTA, Tyr3-octreotate and DOTA, Tyr3-octreotide is that the C-terminal threoninol of DOTA, Tyr3-octreotide is replaced with the amino acid, threonine. As a result, DOTA, Tyr3-octreotate displays improved binding to somatostatin-receptor-positive tissues when compared with DOTA, Tyr3-octreotide [ 49 ]. Gastroenteropancreatic tumors predominantly express subtype 2 of the somatostatin receptor, and DOTA, Tyr3-octreotate has a sixfold to ninefold increased affinity for this receptor subtype in vitro compared with DOTA, Tyr3-octreotide [ 43 , 49 , 50 ]. 177Lu-octreotate was very successful in terms of tumor regression and survival in an experimental model in rats. 177Lu-labeled somatostatin analogs have an important practical advantage over their 90Y-labeled counterparts: 177Lu is not a pure β emitter, but also emits low-energy γ rays, which allows direct posttherapy imaging and dosimetry. Treatment with 177Lu-octreotate resulted in a survival benefit of several years and markedly improved quality of life. PRRT might soon become the therapy of choice for patients with metastatic or inoperable GEPNETs. Nowadays, different somatostatin analogs are available not only for therapeutic purposes but also when labeled with b1-emitters (e.g., 68Ga and 64Cu) for tumor imaging with integrated PET/CT scanners [ 51 , 52 ]. The PET/CT technology provides a highly valuable combination of physiologic and anatomic information and has been shown to impact significantly on the patient's management.
Tumor imaging and PRRT have been extended to many other receptors such as Gastrin-releasing peptide/bombesin (GRP) and Cholecystokinin (CCK) in recent years [ 53 , 54 ]. Radiolabelled receptor antagonists are also emerging as alternatives in this area [ 55 , 56 ].
4. Peptide Vaccines
Active immunization seems to be one of the promising strategies to treat cancer though many approaches based on the employment of immune cells or immune molecules have been studied [ 57 , 58 ]. In the last decade, this idea of vaccinations against cancer has transformed into clinical studies aiming to optimally deliver vaccines based on defined antigens to induce anticancer immunity. This method of treating cancerous cells relies on vaccines consisting of peptides derived from the protein sequence of candidate tumor-associated or specific antigens [ 57 ]. Tumor cells express antigens known as tumor-associated antigens (TAAs) that can be recognized by the host's immune system (T cells). Many TAAs have already been identified and molecularly characterized [ 59 , 60 ]. These TAAs can be injected into cancer patients in an attempt to induce a systemic immune response that may result in the destruction of the cancer growing in different body tissues. This procedure is defined as active immunotherapy or vaccination as the host's immune system is either activated de novo or restimulated to mount an effective, tumor-specific immune reaction that may ultimately lead to tumor regression ( Figure 3 ). Any protein/peptide produced in a tumor cell that has an abnormal structure due to mutation can act as a tumor antigen. Such abnormal proteins are produced due to mutation of the concerned gene. Various clinical studies focus on the therapeutic potential of active immunization or vaccination with TAA peptides in patients with metastatic cancer [ 61 – 63 ].
Most known TAAs are CTL (cytotoxic T lymphocyte also known as CD8+ T-cells or killer T cell) epitopes [ 64 ]. Peptide antigens are usually 8–10 amino acids long with 2-3 primary anchor residues that interact with MHC class 1-molecules and 2-3 residues which bind to T-cell receptor [ 64 , 65 ]. CTLs directed against peptides presented by MHC class 1 molecules constitute powerful effectors of the immune system against tumor cells. The T-cell antigen receptor (TCR) on T cells recognizes the complex of a small peptide located in the antigen-binding groove of an MHC molecule [ 66 ]. MHC molecules (also called human leukocyte antigens (HLAs) in humans) are subdivided into class I molecules, which are found on all nucleated cells and class II molecules, which are found on specialized antigen-presenting cells (APCs) such as dendritic cells, macrophages, B cells, and selected activated endothelial or epithelial cells. CD4+ T cells recognize antigens bound to MHC class II molecules, and, as noted, class II molecules are expressed on APCs that possess the capability of antigen capture through phagocytosis or binding to surface antibody [ 67 , 68 ].
Several of the peptide vaccines have undergone phase I and II clinical trials and have shown promising results in immunological as well as clinical responses. The notable peptide vaccines that have undergone phase I/II/III clinical trials include HER-2/neu immunodominant peptide (lung, breast, or ovarian cancer) [ 69 – 71 ], Mucin-1 (MUC-1, Stimuvax), peptide (breast or colon cancer) [ 72 , 73 ], Carcinoembryonic antigen (colorectal, gastric, breast, pancreatic and non-small-cell lung cancers) [ 74 , 75 ], Prostate-specific membrane antigen (prostate cancer) [ 76 – 78 ], HPV-16 E7 peptide (cervical cancer) [ 79 ], Ras oncoprotein peptide (colorectal and pancreatic carcinomas) [ 80 – 82 ], and Melanoma antigens (Melanoma) [ 62 , 68 , 83 – 85 ]. Another vaccine known as GV-1001 is under development, which is an injectable formulation of a promiscuous MHC class II peptide derived from the telomerase reverse transcriptase catalytic subunit (hTERT). GV-1001 is currently undergoing phase II clinical trials for liver cancer and NSCLC (non-small-cell lung cancer) as well as a phase III trial for pancreatic cancer [ 86 ].
The peptide vaccines are relatively less expensive, easy to manufacture and manipulate, are of defined structure, and being synthetic in nature do not have a problem of batch-to-batch variation. The major disadvantage of the peptide vaccines is their weak immunogenicity. Several strategies such as epitope enhancement, use of various T-cell epitopes, adjuvants, incorporation of costimulatory molecules, ex vivo loading into antigen presenting cells are being explored to enhance the immunogenicity and efficacy of the peptide vaccines [ 73 – 86 ].
5. Peptide as Cytotoxic Drug Carrier
Several peptide receptors are known which can be used as potential drug targets in cancer therapy [ 53 – 56 , 87 , 88 ]. The role of somatostatin receptors has already been discussed in the previous section for peptide receptor radionuclide therapy (PRRT). Similarly, a peptide can be conjugated to a cytotoxic drug to deliver it to a cancer cell expressing the corresponding peptide receptor. Such peptides are known as cell targeting peptides as they can specifically target a cell expressing its receptor. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin can be targeted to certain tumors possessing receptors for those peptides and therefore are more selective for killing cancer cells [ 89 , 90 ]. For example, a potential drug candidate, AEZS-108, couples a peptide LHRH with the chemotherapeutic agent doxorubicin to directly target cells that express LH-RH receptors, specifically prostate cancer cells [ 91 , 92 ]. A list of different peptide receptors, their subtypes, tumors in which these receptors are expressed, and some of the targeting agents used are depicted in Table 2 [ 93 ]. Most of the studies so far are in the area of radionuclide therapy and imaging though a few studies examined the transport of cytotoxic drugs such as AN-201 and doxorubicin [ 94 ]. Nevertheless, these receptors provide good platform for the cell-specific delivery of chemotherapeutic agents.
Apart from peptides that can selectively bind to the previous peptide receptors, many other peptides which are relevant to cancer treatment were discovered in recent years. These peptides obtained by in vivo phage display technology are known as homing peptides as they home very specifically to various normal organs or diseased tissues [ 95 – 97 ]. The RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) peptides represent the first generation of homing peptides [ 95 ]. Tumor homing of the RGD and NGR peptides appears to be independent of the tumor type, demonstrating that the receptors for these peptides are upregulated during angiogenesis. The RGD motif was originally discovered in peptides that bind to different integrins. The RGD peptide was shown to home to malignant melanoma, breast carcinoma xenografts, and rheumatoid arthritis model indicating that they recognize angiogenic vessels in general. The RGD peptides have high affinity towards the α v integrin receptors in the angiogenic vasculature. The NGR motif was identified in an in vivo screen on human breast carcinoma xenografts [ 96 ]. It was originally identified as a cell adhesion motif, and it homes selectively to tumor blood vessels and other types of angiogenic vessels. The receptor for the NGR peptide is a peptidase, aminopeptidase N (APN), expression of which is upregulated in the angiogenic blood vessels. Several other peptides such as TAASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteoglycan NG2 receptor) and F3 peptide (31 amino acid peptide that binds to cell surface-expressed nucleolin receptor) were identified thereafter [ 98 , 99 ]. Recently, homing peptides with cell-penetrating ability were discovered [ 99 – 101 ]. Cell-penetrating peptides (CPPs) are small peptides, generally less than 30 amino acids long, that internalize very efficiently into all cells they come into contact with [ 102 ]. These internalizing homing peptides are similar to the classic cell-penetrating peptides, such as the transcription-transactivating (Tat) protein of HIV-1, and penetrating with an important exception: the internalization of the homing peptides is cell-type-specific. Both the F3 and LyP-1 (CGNKRTRGC) peptides are cell-type-specific CPPs [ 99 – 101 ]. They are able to internalize tumor cells and blood (F3) or lymphatic (LyP-1) endothelial cells in the tumors they home to.
Homing peptides have been successfully used as delivery vehicles to target imaging agents, drug molecules, oligonucleotides, liposomes, and inorganic nanoparticles to tumors and other tissues [ 97 , 103 , 104 ]. One drug that has been delivered using RGD and NGR peptides is the tumor necrosis factor- α (TNF- α ) that has potent antitumor activity [ 98 , 105 ]. The clinical use of TNF- α itself as an anticancer drug is limited to local treatments due to its dose-limiting systemic toxicity. RGD and NRG peptide-targeted TNF- α treatment decreased tumor growth with smaller doses than free TNF- α . The antitumor activity of NGR-TNF- α was also studied in combination with various chemotherapeutic drugs: doxorubicin and melphalan as well as cisplatin, paclitaxel, and gemcitabine and compared to the efficacy of the chemotherapeutic drugs alone in various murine tumor models [ 105 ]. The results showed that targeted delivery of low doses of NGR-TNF- α to tumor vasculature increased the efficacy of various drugs acting via different mechanisms. Moreover, transgenic mice with androgen-independent prostate carcinoma (TRAMP-C1) were treated with repeated cycles of doxorubicin, administered either alone or following NGR-TNF- α administration. Pretreatment with NGR-TNF- α significantly expanded the therapeutic index of doxorubicin and significantly delayed tumor growth without increasing drug-related toxicity. The RGD homing peptide has also been conjugated to doxorubicin [ 97 , 106 ]. This treatment inhibited tumor growth and prolonged the lifespan of tumor-bearing animals. Again the doxorubicin-RGD conjugate was less toxic than doxorubicin alone or doxorubicin conjugated to a control peptide. Conjugation of IL-12 (Interleukin-12) to the CDCRGDCFC (RGD-4C) peptide, a specific ligand for α v β 3 integrin, targets IL-12 directly to tumor neovasculature [ 107 ]. This fusion protein stimulated interferon- γ production in vitro and in vivo , suggesting biological activity consistent with IL-12. Localization of IL-12 to the angiogenic vasculature significantly enhanced the antiangiogenic effect in corneal angiogenesis assay, augmented antitumor activity in a neuroblastoma model, and decreased toxicity of the IL-12.
A number of clinical trials based on RGD and NGR targeted drug delivery are currently ongoing or recruiting patients [ 108 – 110 ]. For example, a phase Ib study was conducted to verify the safety of NGR peptide-targeted hTNF in combination with doxorubicin in treatment of refractory/resistant solid tumors [ 108 ]. Fifteen patients received various doses of a combination of NGR-targeted hTNF and doxorubicin intravenously. One partial response (7%) and ten stable diseases (66%) lasting for a median duration of 5.6 months were observed. These results prompted plans for the phase II development ( http://clinicaltrials.gov/ ). In addition, a phase III trial on newly diagnosed glioblastoma has been started [ 97 ]. A recently identified peptide called iRGD is able to specifically recognize and penetrate cancerous tumors but not normal tissues [ 111 ]. Chlorotoxin (a 36 amino acid peptide derived from scorpion venom) binds preferentially to glioma cells compared with nonneoplastic cells or normal brain has allowed the development of new methods for the treatment and diagnosis of cancer [ 112 ].
6. Anticancer Peptides
Direct use of peptide as a therapeutic agent to treat cancer is gaining momentum in the recent years. Anticancer activity of different peptides is attributed to a variety of mechanisms that restrict tumor growth. The mechanism involves the inhibition of angiogenesis, protein-protein interactions, enzymes, proteins, signal transduction pathways, or gene expression [ 113 – 120 ]. Another category of anti-cancer peptides is peptide antagonists which can preferentially bind to a known receptor [ 121 , 122 ]. Moreover “pro-apoptotic” peptides mediate significant induction of apoptosis (programmed cell death) in tumors [ 123 – 125 ].
Angiogenesis involves the migration, growth, and differentiation of endothelial cells, which line the inside wall of blood vessels. There is a tremendous effort to discover angiogenesis inhibitors, based on peptides as the safest and least toxic therapy for diseases associated with abnormal angiogenesis [ 113 ]. Angiogenesis requires the binding of signaling molecules, such as vascular endothelial growth factor (VEGF), to receptors on the surface of normal endothelial cells. When VEGF and other endothelial growth factors bind to their receptors on endothelial cells, signals within these cells are initiated that promote the growth and survival of new blood vessels. Angiogenesis inhibitors interfere with various steps in this process. A number of ongoing clinical trials in this area focus on peptides derived from extracellular matrix proteins, growth factors and growth factor receptors, coagulation cascade proteins, chemokines, and type I Thrombospondin domain containing proteins and serpins [ 113 , 114 ]. Recently it was found that angiotensin-(1–7) can stop lung cancer tumor growth in mice by inhibiting blood vessel formation [ 126 ]. The antiangiogenic agent cilengitide (Merck) is a derivative of the RGD peptide [ 127 – 130 ]. It is the inner salt of a cyclized RGD pentapeptide (cyclo-[Arg-Gly-Asp-DPhe-(NMeVal)]) that is selective for α v integrins, which are important in angiogenesis. It is currently under phase II trial for the treatment of glioblastoma and refractory brain tumors in children. Another peptide, ATN-161 (Ac-PHSCN-NH2), is in early phase II trials for cancer [ 120 ]. It binds to and inhibits integrins involved in tumor progression (a5ß1, avß3, and avß5), while not inhibiting adhesion as it is not based on the RGD sequence [ 131 ]. A dipeptide, L-glutamine L-tryptophan (IM862) that is made normally in the thymus gland, has shown antiangiogenic properties. Though it was shown recently to be ineffective against AIDS-Kaposi's sarcoma in a phase III trial, it still holds promise for other forms of cancer [ 132 , 133 ].
BN/GRP (bombesin/gastrin-releasing peptide) peptides were shown to bind selectively to the G-protein-coupled receptors on the cell surface, stimulating the growth of various malignancies in murine and human cancer models [ 134 , 135 ]. Thus, it has been proposed that the secretion of BN/GRP by neuroendocrine cells might be responsible for the development and progression of prostate cancer to androgen independence. GRP is widely distributed in lung and gastrointestinal tracts. It is produced in small cell lung cancer (SCLC), breast, prostatic, and pancreatic cancer and functions as a growth factor. The involvement of bombesin-like peptides in the pathogenesis of a wide range of human tumors, their function as autocrine/paracrine tumoural growth factors, and the high incidence of BN/GRP receptors in various human cancers prompted the design and synthesis of BN/GRP receptor (GRPR) antagonists such as RC-3095, RC-3940-II, and RC-3950 [ 136 – 138 ]. Recently, many researchers are focusing on the development of GHRH (growth hormone releasing hormone—a hypothalamic polypeptide) antagonists as potential anti-cancer therapeutics since the GHRH is produced by various human tumors, including prostate cancer, and seems to exert an autocrine/paracrine stimulatory effect on tumors [ 139 , 140 ].
Recently, scientists have designed peptides to target the protein-protein interface of a key enzyme in DNA synthesis crucial for cancer growth [ 141 ]. The peptides act by a novel inhibitory mechanism and curb cancer cell growth in drug-resistant ovarian cancer cells. These octapeptides specifically target the protein-protein interface of thymidylate synthase. Thymidylate synthase is composed of two identical polypeptide chains; that is, it is a homodimer. The peptides stabilize the inactive form of the enzyme, show a novel mechanism of inhibition for homodimeric enzymes, and inhibit cell growth in drug sensitive and resistant cancer cell lines [ 141 ].
Cisplatin, cisplatinum, or cis -diamminedichloroplatinum(II) is the first member of a class of platinum-containing anti-cancer drugs. These platinum complexes react in vivo , binding to and causing crosslinking of DNA, which ultimately triggers apoptosis (programmed cell death). Recently, Pt (IV)-peptide conjugates were found to be good inhibitors of cellular proliferation when compared to a nontargeting platinum(IV) parent compound, showing that its relatively low cytotoxicity is greatly improved by addition of the peptides [ 142 ]. (KLAKLAK)2 is an antimicrobial apoptosis-inducing peptide that upon internalization causes mitochondrial swelling and disruption of the mitochondrial membrane leading to apoptosis [ 123 , 124 , 143 ]. The RGD-(KLAKLAK)2 and NGR-(KLAKLAK)2 were especially toxic to angiogenic endothelial cells leading to reduced tumor growth and metastases as well as prolonged survival. LyP-1 is unique among the tumor homing peptides since it has cytotoxic activity on its own [ 144 ]. When injected into the tail vein of mice with MDA-MB-435 breast cancer xenografts, LyP-1 peptide by itself inhibited tumor growth and reduced the number of lymphatic vessels, thus demonstrating a cytotoxic activity of the peptide.
7. Other Anticancer Drugs Closely Related to Peptides
Bortezomib is the first therapeutic proteasome inhibitor to be tested in humans [ 21 , 145 , 146 ]. It is approved in the USA for treating relapsed multiple myeloma and mantle cell lymphoma (2003). In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease. The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine, and leucine with a boronic acid instead of a carboxylic acid. Mifamurtide (Mepact) is a drug against osteosarcoma, which is lethal in about a third of cases [ 147 ]. The drug was approved in Europe in March 2009 and is not currently approved in the USA. Mifamurtide is a fully synthetic derivative of muramyl dipeptide (MDP) the smallest naturally occurring immune stimulatory component of cell walls from Mycobacterium species. The side chains of the molecule give it a longer elimination half-life than the natural substance. Being a phospholipid, it accumulates in the lipid bilayer of the liposomes in the infusion. It recognizes muramyl dipeptide and simulates a bacterial infection by binding to NOD2 (NOD2 is a pattern recognition receptor which is found in several kinds of white blood cells, mainly monocytes and macrophages) activating white cells [ 148 ]. This results in an increased production of TNF- α , interleukin 1, interleukin 6, interleukin 8, interleukin 12, and other cytokines, as well as ICAM-1. The activated white cells attack cancer cells, but not other cells. Brentuximab Vedotin, an antibody drug conjugate (ADS) approved in 2011, is a chimeric monoclonal antibody, brentuximab (which targets the cell-membrane protein CD30) linked to three to five units of the antimitotic agent monomethyl auristatin E. The linker here is a valine-citrulline dipeptide which is cleaved by cathepsin once the conjugate has entered a tumor cell. The antimitotic agent monomethyl auristatin E can be considered as a peptidomimetic [ 149 , 150 ].
8. Conclusion
In conclusion, peptides are poised to make a huge impact in near future in the area of cancer treatment and diagnosis. Targeted chemotherapy and drug delivery techniques are emerging as an excellent tool in minimizing problems with the conventional chemotherapy. Along with different peptide-based cancer therapeutics already available for patients, a number of peptide-based therapies such as cancer vaccines, tumor targeting with cytotoxic drugs and radioisotopes, and anti-angiogenic peptides are currently on clinical trials and are expected to yield positive results. Stimuvax (palmitoylated peptide vaccine against nonsmall lung cancer, Merck), Primovax (peptide cancer vaccine, Pharmexa), Melanotan (precancerous actinic keratosis, Clinuvel), and Cilengitide (Glioblastoma, Merck) are some examples of potential peptides in late clinical trials. Due to the tremendous advancement in the large scale synthesis of peptides it will be possible to make peptide-based anti-cancer drugs more affordable to patients. In recent years combination therapy is emerging as an important strategy to fight cancer as just one method may not be efficient enough to cure the disease completely or prevent recurrence [ 151 ]. In the hope of achieving synergistic effects, combinations of antiangiogenesis with traditional chemotherapy are currently being pursued in clinical trials [ 151 – 155 ]. For example, cilengitide was used in a phase I/IIa combination trial, which combined cilengitide with radiotherapy and temozolomide for newly diagnosed Glioblastoma patients resulting in better overall survival (OS) rates [ 152 ]. ATN-161 enhances the activity of radiation and chemotherapy and is progressing to a phase II trial for head and neck cancer [ 153 ]. Encouraging data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy, may improve efficacy [ 154 ] in cancer treatment and management.
1 Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA Cancer Journal for Clinicians 2011 61 2 69 90 2-s2.0-79952232216 10.3322/caac.20107 21296855
2 Global cancer facts & figures 2nd edition, American Cancer Society, http://www.cancer.org/
3 Vogelstein B Kinzler KW Cancer genes and the pathways they control Nature Medicine 2004 10 8 789 799 2-s2.0-4043181214 10.1038/nm1087 15286780
4 Folkman J Angiogenesis in cancer, vascular, rheumatoid and other disease Nature Medicine 1995 1 1 27 31 2-s2.0-0028929803 10.1038/nm0195-27 7584949
5 Kakde D Jain D Shrivastava V Kakde R Patil AT Cancer therapeutics—opportunities, challenges and advances in drug delivery Journal of Applied Pharmaceutical Science 2011 1 9 1 10
6 Enbäck J Laakkonen P Tumour-homing peptides: tools for targeting, imaging and destruction Biochemical Society Transactions 2007 35 4 780 783 2-s2.0-34548168881 17635147 10.1042/BST0350780
7 Dorsam RT Gutkind JS G-protein-coupled receptors and cancer Nature Reviews Cancer 2007 7 2 79 94 2-s2.0-33846474121 17251915 10.1038/nrc2069
8 Aina OH Sroka TC Chen ML Lam KS Therapeutic cancer targeting peptides Biopolymers 2002 66 3 184 199 2-s2.0-0036416110 12385037 10.1002/bip.10257
9 Meng L Yang L Zhao X Zhang L Zhu H Targeted delivery of chemotherapy agents using a liver cancer-specific aptamer PLoS One 2012 7 4 e33434 10.1371/journal.pone.0033434 PMC3338807 22558072
10 Zhang XX Eden HS Chen X Peptides in cancer nanomedicine: drug carriers, targeting ligands and protease substrates Journal of Controlled Release 2012 159 2 13 22056916 10.1016/j.jconrel.2011.10.023 PMC3288222
11 Vlieghe P Lisowski V Martinez J Khrestchatisky M Synthetic therapeutic peptides: science and market Drug Discovery Today 2010 15 1-2 40 56 2-s2.0-74149094591 19879957 10.1016/j.drudis.2009.10.009
12 Qiu XQ Wang H Cai B Wang LL Yue ST Small antibody mimetics comprising two complementarity-determining regions and a framework region for tumor targeting Nature Biotechnology 2007 25 8 921 929 2-s2.0-34547742068 10.1038/nbt1320 17676038
13 Allen TM Ligand-targeted therapeutics in anticancer therapy Nature Reviews Cancer 2002 2 750 763 12360278 10.1038/nrc903
14 Pastan I Hassan R Fitzgerald DJ Kreitman RJ Immunotoxin therapy of cancer Nature Reviews Cancer 2006 6 559 565 16794638 10.1038/nrc1891
15 Thorpe PE Vascular targeting agents as cancer therapeutics Cancer Research 2004 10 415 427 10.1158/1078-0432.ccr-0642-03 14760060
16 Mori T Cancer-specific ligands identified from screening of peptide-display libraries Current Pharmaceutical Design 2004 10 19 2335 2343 15279612 10.2174/1381612043383944
17 Reff ME Hariharan K Braslawsky G Future of monoclonal antibodies in the treatment of hematologic malignancies Cancer Control 2002 9 2 152 166 2-s2.0-0036240463 11965235 10.1177/107327480200900207
18 Thayer AM Improving peptides Chemical and Engineering News 2011 89 13 20
19 Borghouts C Kunz C Groner B Current strategies for the development of peptide-based anti-cancer therapeutics Journal of Peptide Science 2005 11 11 713 726 2-s2.0-28044454553 16138387 10.1002/psc.717
20 Peptide Therapeutics Foundation Development trends for peptide therapeutics 2010 San Diego, Calif, USA
21 Adams J Kauffman M Development of the proteasome inhibitor Velcade (Bortezomib) Cancer Investigation 2004 22 2 304 311 2-s2.0-2642551603 15199612 10.1081/cnv-120030218
22 Meyers PA Schwartz CL Krailo M Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate Journal of Clinical Oncology 2005 23 9 2004 2011 2-s2.0-20144380941 15774791 10.1200/JCO.2005.06.031
23 Miller WR Scott WN Morris R Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist Nature 1985 313 5999 231 233 2-s2.0-0021971578 2982100 10.1038/313231a0
24 Schally AV Comaru-Schally AM Plonowski A Nagy A Halmos G Rekasi Z Peptide analogues in the therapy of prostate cancer Prostate 2000 5 2 158 166 10.1002/1097-0045(20001001)45:2<158::aid-pros10>3.0.co;2-k 11027415
25 Crawford ED Hormonal therapy in prostate cancer: historical approaches Reviews in Urology 2004 6 7 S3 S11 PMC1472891 16985934
26 Engel JB Schally AV Drug insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone Nature Clinical Practice Endocrinology and Metabolism 2007 3 2 157 167 2-s2.0-33846414318 10.1038/ncpendmet0399 17237842
27 Sogani PC Fair WR Treatment of advanced prostatic cancer Urologic Clinics of North America 1987 14 2 353 371 2-s2.0-0023179450 2953100
28 Wirth M Froehner M A review of studies of hormonal adjuvant therapy in prostate cancer European Urology 1999 36 2 14 19 2-s2.0-0032835977 10.1159/000052338 10529561
29 Lee TH Lin YH Seow KM Hwang JL Tzeng CR Yang YS Effectiveness of cetrorelix for the prevention of premature luteinizing hormone surge during controlled ovarian stimulation using letrozole and gonadotropins: a randomized trial Fertility and Sterility 2008 90 1 113 120 2-s2.0-45849141630 18054932 10.1016/j.fertnstert.2007.06.029
30 Debruyne F Bhat G Garnick MB Abarelix for injectable suspension: first-in-class gonadotropin-releasing hormone antagonist for prostate cancer Future Oncology 2006 2 6 677 696 2-s2.0-33845662144 17155895 10.2217/14796694.2.6.677
31 Broqua P Riviere PJM Michael Conn P Rivier JE Aubert ML Junien JL Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: Degarelix Journal of Pharmacology and Experimental Therapeutics 2002 301 1 95 102 2-s2.0-0036129344 11907162 10.1124/jpet.301.1.95
32 Strowski MZ Blake AD Function and expression of somatostatin receptors of the endocrine pancreas Molecular and Cellular Endocrinology 2008 286 1-2 169 179 2-s2.0-43749121851 18375050 10.1016/j.mce.2008.02.007
33 Saltz L Trochanowski B Buckley M Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors Cancer 1993 72 1 244 248 2-s2.0-0027198659 8389666 10.1002/1097-0142(19930701)72:1<244::aid-cncr2820720143>3.0.co;2-q
34 Faiss S Pape UF Böhmig M Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—the International Lanreotide and Interferon Alfa Study Group Journal of Clinical Oncology 2003 21 14 2689 2696 2-s2.0-0043132282 12860945 10.1200/JCO.2003.12.142
35 Hoyer D Bell GI Berelowitz M Classification and nomenclature of somatostatin receptors Trends in Pharmacological Sciences 1995 16 3 86 88 2-s2.0-0028955742 7792934 10.1016/s0165-6147(00)88988-9
36 Rufini V Calcagni ML Baum RP Imaging of neuroendocrine tumors Seminars in Nuclear Medicine 2006 36 3 228 247 2-s2.0-33744547026 16762613 10.1053/j.semnuclmed.2006.03.007
37 Virgolini I Traub T Novotny C Experience with Indium-111 and Yttrium-90-labeled somatostatin analogs Current Pharmaceutical Design 2002 8 20 1781 1807 2-s2.0-0035993440 12171531 10.2174/1381612023393756
38 Bushnell DL Menda Y Madsen MT 99mTc-depreotide tumour uptake in patients with non-Hodgkin’s lymphoma Nuclear Medicine Communications 2004 25 8 839 843 2-s2.0-4143134188 15266180 10.1097/01.mnm.0000126628.01919.f9
39 Kwekkeboom D Krenning EP de Jong M Peptide receptor imaging and therapy Journal of Nuclear Medicine 2000 41 1704 1713 11038002
40 Krenning EP de Jong M Kooij PP Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy Annals of Oncology 1999 10 2 23 29 10399029 10.1093/annonc/10.suppl_2.s23
41 Kwekkeboom DJ Teunissen JJ Bakker WH Radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors Journal of Clinical Oncology 2005 23 12 2754 2762 2-s2.0-21044451724 15837990 10.1200/JCO.2005.08.066
42 Pauwels S Barone R Walrand S Practical dosimetry of peptide receptor radionuclide therapy with 90Y-labeled somatostatin analogs Journal of Nuclear Medicine 2005 46 1 S92 S98 2-s2.0-14844338706 15653657
43 Esser JP Krenning EP Teunissen JJM Comparison of [177Lu-DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: ehich peptide is preferable for PRRT? European Journal of Nuclear Medicine and Molecular Imaging 2006 33 11 1346 1351 2-s2.0-33750307975 16847654 10.1007/s00259-006-0172-9
44 Otte A Jermann E Behe M DOTATOC: a powerful new tool for receptormediated radionuclide therapy European Journal of Nuclear Medicine 1997 24 792 795 9211767 10.1007/BF00879669
45 De Jong M Valkema R Jamar F Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings Seminars in Nuclear Medicine 2002 32 2 133 140 2-s2.0-0036226273 11965608 10.1053/snuc.2002.31027
46 Nicolas G Giovacchini G Müller-Brand J Forrer F Targeted radiotherapy with radiolabeled somatostatin analogs Endocrinology and Metabolism Clinics of North America 2011 40 1 187 204 2-s2.0-79951741757 21349419 10.1016/j.ecl.2010.12.006
47 Grozinsky-Glasberg S Shimon I Korbonits M Grossman AB Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms Endocrine-Related Cancer 2008 15 3 701 720 2-s2.0-53849134827 18524947 10.1677/ERC-07-0288
48 Wild D Mäcke HR Waser B 68Ga-DOTANOC: a first compound for PET imaging with high affinity for somatostatin receptor subtypes 2 and 5 European Journal of Nuclear Medicine and Molecular Imaging 2005 32 6 p. 724 2-s2.0-21244490346 10.1007/s00259-004-1697-4 15551131
49 Kwekkeboom DJ De Herder WW Kam BL Treatment with the radiolabeled somatostatin analog [177Lu- DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival Journal of Clinical Oncology 2008 26 13 2124 2130 2-s2.0-43749091955 18445841 10.1200/JCO.2007.15.2553
50 Van Essen M Krenning EP Kooij PP Effects of therapy with [177Lu-DOTA0, Tyr 3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma Journal of Nuclear Medicine 2006 47 10 1599 1606 2-s2.0-34147182966 17015894
51 Baum RP Prasad V Hommann M Hörsch D Receptor PET/CT imaging of neuroendocrine tumors Cancer Research 2008 170 225 242 2-s2.0-38449118147 10.1007/978-3-540-31203-1_18 18019630
52 Buchmann I Henze M Engelbrecht S Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours European Journal of Nuclear Medicine and Molecular Imaging 2007 34 10 1617 1626 2-s2.0-34748835270 17520251 10.1007/s00259-007-0450-1
53 Van De Wiele C Phonteyne P Pauwels P Gastrin-releasing peptide receptor imaging in human breast carcinoma versus immunohistochemistry Journal of Nuclear Medicine 2008 49 2 260 264 2-s2.0-38949192477 18199617 10.2967/jnumed.107.047167
54 Zhang H Chen J Waldherr C Synthesis and evaluation of bombesin derivatives on the basis of pan-bombesin peptides labeled with Indium-111, Lutetium-177, and Yttrium-90 for targeting bombesin receptor-expressing tumors Cancer Research 2004 64 18 6707 6715 2-s2.0-4644360336 15374988 10.1158/0008-5472.CAN-03-3845
55 Ginj M Zhang H Waser B Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors Proceedings of the National Academy of Sciences 2006 103 16436 16441 10.1073/pnas.0607761103 PMC1618814 17056720
56 Wild D Fani M Behe M Brink I Rivier JE Reubi JC First clinical evidence that imaging with somatostatin receptor antagonists is feasible Journal of Nuclear Medicine 2011 52 1412 14217 21852357 10.2967/jnumed.111.088922
57 Henderson RA Mossman S Nairn N Cheever MA Cancer vaccines and immunotherapies: emerging perspectives Vaccine 2005 23 2359 2362 15755628 10.1016/j.vaccine.2005.01.082
58 Berzoksky JA Ahlers JD Belyakov IM Strategies for designing and optimizing new generation vaccines Nature 2001 1 209 219 10.1038/35105075 11905830
59 Hareuveni M Gautier C Kieny MP Wreschner D Chambon P Lathe R Vaccination against tumor cells expressing breast cancer epithelial tumor antigen Proceedings of the National Academy of Sciences of the United States of America 1990 87 23 9498 9502 2-s2.0-0025604608 2251291 10.1073/pnas.87.23.9498 PMC55194
60 Coulie PG Hanagiri T Takenoyama M From tumor antigens to immunotherapy International Journal of Clinical Oncology 2001 6 4 163 170 2-s2.0-0034799697 11706553 10.1007/pl00012101
61 Eisenbach L Bar-Haim E El-Shami K Antitumor vaccination using peptide based vaccines Immunology Letters 2000 74 1 27 34 2-s2.0-0034666235 10996624 10.1016/s0165-2478(00)00245-5
62 Parmiani G Castelli C Dalerba P Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? Journal of the National Cancer Institute 2002 94 11 805 818 2-s2.0-0037024461 12048268 10.1093/jnci/94.11.805
63 Beck A Klinguer-Hamour C Bussat MC Peptides as tools and drugs for immunotherapies Journal of Peptide Science 2007 13 9 588 602 2-s2.0-34848837625 17602441 10.1002/psc.852
64 Gao GF Jakobsen BK Molecular interactions of coreceptor CD8 and MHC class I: the molecular basis for functional coordination with the T-cell receptor Immunology Today 2000 21 12 630 636 2-s2.0-0034517387 11114424 10.1016/s0167-5699(00)01750-3
65 Cho HI Celis E Optimized peptide vaccines eliciting extensive CD8 T-cell responses with therapeutic antitumor effects Cancer Research 2009 69 23 9012 9019 2-s2.0-71549172516 19903852 10.1158/0008-5472.CAN-09-2019 PMC2789207
66 Apanius V Penn D Slev PR Ruff LR Potts WK The nature of selection on the major histocompatibility complex Critical Reviews in Immunology 1997 17 2 179 224 2-s2.0-0030977721 9094452 10.1615/critrevimmunol.v17.i2.40
67 Oshima M Deitiker P Ashizawa T Atassi MZ Vaccination with a MHC class II peptide attenuates cellular and humoral responses against tAChR and suppresses clinical EAMG Autoimmunity 2002 35 3 183 190 2-s2.0-0035993102 12389643 10.1080/08916930290022270
68 Banchereau J Palucka AK Dhodapkar M Immune and clinical responses in patients with metastatic melanoma to CD34 + progenitor-derived dendritic cell vaccine Cancer Research 2001 61 17 6451 6458 11522640
69 Knutson KL Schiffman K Disis ML Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients Journal of Clinical Investigation 2001 107 4 477 484 2-s2.0-0035113705 11181647 10.1172/JCI11752 PMC199268
70 Sole K HER-2/neu peptide vaccine for the prevention of prostate cancer recurrence Nature Reviews Urology 2006 3 p. 6
71 Hueman MT Dehqanzada ZA Novak TE Phase I clinical trial of a HER-2/neu peptide (E75) vaccine for the prevention of prostate-specific antigen recurrence in high-risk prostate cancer patients Clinical Cancer Research 2005 11 20 7470 7479 2-s2.0-27144559991 16243821 10.1158/1078-0432.CCR-05-0235
72 Ramanathan RK Lee KM McKolanis J Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer Cancer Immunology, Immunotherapy 2005 54 3 254 264 2-s2.0-19944433959 15372205 10.1007/s00262-004-0581-1 PMC11034344
73 Yamamoto K Ueno T Kawaoka T MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer Anticancer Research 2005 25 5 3575 3579 2-s2.0-23344445706 16101182
74 Ma Y Zhu ZH Situ DR Hu Y Rong TH Wang J Expression and prognostic relevance of tumor carcino-embryonic antigen in stage IB non-small cell lung cancer Journal of Thoracic Disease 2012 4 5 490 496 23050113 10.3978/j.issn.2072-1439.2012.09.01 PMC3461079
75 Grunnet M Sorensen JB Carcinoembryonic antigen (CEA) as tumor marker in lung cancer Lung Cancer 2012 76 2 138 143 22153832 10.1016/j.lungcan.2011.11.012
76 Weber JS Vogelzang NJ Ernstoff MS A phase 1 study of a vaccine targeting preferentially expressed antigen in melanoma and prostate-specific membrane antigen in patients with advanced solid tumors Journal of Immunotherapy 2011 34 7 556 567 21760528 10.1097/CJI.0b013e3182280db1 PMC3709852
77 Garetto S Sizzano F Brusa D Tizzani A Malavasi F Matera L Binding of prostate-specific membrane antigen to dendritic cells: a critical step in vaccine preparation Cytotherapy 2009 11 8 1090 1100 2-s2.0-71149112331 19929472 10.3109/14653240903164971
78 Akhtar NH Pail O Saran A Tyrell L Tagawa ST Prostate-specific membrane antigen-based therapeutics Advances in Urology 2012 2012 9 pages 973820 10.1155/2012/973820 PMC3145341 21811498
79 Muderspach L Wilczynski S Roman L A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive Clinical Cancer Research 2000 6 9 3406 3416 2-s2.0-0033813525 10999722
80 Khleif SN Abrams SI Hamilton JM A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors Journal of Immunotherapy 1999 22 2 155 165 2-s2.0-0032975450 10093040 10.1097/00002371-199903000-00007
81 Gjertsen MK Gaudernack G Mutated ras peptides as vaccines in immunotherapy of cancer Vox Sanguinis 1998 74 2 489 495 2-s2.0-0031818750 9704487 10.1111/j.1423-0410.1998.tb05462.x
82 Abrams SI Hand PH Tsang KY Schlom J Mutant ras epitopes as targets for cancer vaccines Seminars in Oncology 1996 23 1 118 134 2-s2.0-0030005037 8607022
83 Kaufman HL Vaccines for melanoma and renal cell carcinoma Seminars in Oncology 2012 39 3 263 275 22595049 10.1053/j.seminoncol.2012.02.011
84 Markowicz S Nowecki ZI Rutkowski P Adjuvant vaccination with melanoma antigen-pulsed dendritic cells in stage III melanoma patients Medical Oncology 2012 29 2966 2977 22302285 10.1007/s12032-012-0168-1
85 Yang JC Melanoma vaccines Cancer Journal 2011 17 5 277 282 10.1097/PPO.0b013e3182325f72 21952276
86 Nava-Parada P Emens LA GV-1001, an injectable telomerase peptide vaccine for the treatment of solid cancers Current Opinion in Molecular Therapeutics 2007 9 5 490 497 2-s2.0-35348839053 17932813
87 Gotthardt M Béhé MP Grass J Added value of gastrin receptor scintigraphy in comparison to somatostatin receptor scintigraphy in patients with carcinoids and other neuroendocrine tumours Endocrine-Related Cancer 2006 13 4 1203 1211 2-s2.0-33846820574 17158765 10.1677/erc.1.01245
88 Reubi JC Targeting CCK receptors in human cancers Current Topics in Medicinal Chemistry 2007 7 1239 1242 17584145 10.2174/156802607780960546
89 Schally AV Nagy A Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors European Journal of Endocrinology 1999 141 1 1 14 2-s2.0-0032797051 10407215 10.1530/eje.0.1410001
90 Schally AV Nagy A Chemotherapy targeted to cancers through tumoral hormone receptors Trends in Endocrinology and Metabolism 2004 15 7 300 310 2-s2.0-4444274816 15350601 10.1016/j.tem.2004.07.002
91 Schally AV Engel JB Emons G Block NL Pinski J Use of analogs of peptide hormones conjugated to cytotoxic radicals for chemotherapy targeted to receptors on tumors Current Drug Delivery 2011 8 1 11 25 2-s2.0-78650873834 21034424 10.2174/156720111793663598
92 Emons G Tomov S Harter P Phase II study of AEZS-108 (AN-152), a targeted cytotoxic LHRH analog, in patients with LHRH receptor-positive platinum resistant ovarian cancer Journal of Clinical Oncology 2010 28 15
93 Reubi JC Peptide receptors as molecular targets for cancer diagnosis and therapy Endocrine Reviews 2003 24 4 389 427 12920149 10.1210/er.2002-0007
94 Szepeshazi K Schally AV Halmos G Targeting of cytotoxic somatostatin analog AN-238 to somatostatin receptor subtypes 5 and/or 3 in experimental pancreatic cancers Clinical Cancer Research 2001 7 9 2854 2861 2-s2.0-0034803184 11555603
95 Zitzmann S Ehemann V Schwab M Arginine-glycine-aspartic acid (RGD)-peptide binds to both tumor and tumor-endothelial cells in vivo Cancer Research 2002 62 18 5139 5143 2-s2.0-0037105767 12234975
96 Temminga K Schiffelers RM Molemad G Kok RJ RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature Drug Resistance Updates 2005 8 381 402 16309948 10.1016/j.drup.2005.10.002
97 Laakkonen P Vuorinen K Homing peptides as targeted delivery vehicles Integrative Biology 2010 2 7-8 326 337 2-s2.0-77955535761 20657951 10.1039/c0ib00013b
98 Burg MA Pasqualini R Arap W Ruoslahti E Stallcup WB NG2 proteoglycan-binding peptides target tumor neovasculature Cancer Research 1999 59 12 2869 2874 2-s2.0-0033564799 10383148
99 Porkka K Laakkonen P Hoffman JA Bernasconi M Ruoslahti E A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo Proceedings of the National Academy of Sciences of the United States of America 2002 99 11 7444 7449 2-s2.0-0037188542 12032302 10.1073/pnas.062189599 PMC124250
100 Zhang L Giraudo E Hoffman JA Hanahan D Ruoslahti E Lymphatic zip codes in premalignant lesions and tumors Cancer Research 2006 66 11 5696 5706 2-s2.0-33745257023 16740707 10.1158/0008-5472.CAN-05-3876
101 Laakkonen P Porkka K Hoffman JA Ruoslahti E A tumor-homing peptide with a targeting specificity related to lymphatic vessels Nature Medicine 2002 8 7 751 755 2-s2.0-0036063778 10.1038/nm720 12053175
102 Wagstaff KM Jans DA Protein transduction: cell penetrating peptides and their therapeutic applications Current Medicinal Chemistry 2006 13 12 1371 1387 2-s2.0-33646525645 16719783 10.2174/092986706776872871
103 Chen K Chen X Integrin targeted delivery of chemotherapeutics Theranostics 2011 1 189 200 21547159 10.7150/thno/v01p0189 PMC3086622
104 Garanger E Boturyn D Dumy P Tumor targeting with RGD peptide ligands-design of new molecular conjugates for imaging and therapy of cancers Anti-Cancer Agents in Medicinal Chemistry 2007 7 5 552 558 2-s2.0-35748963560 17896915 10.2174/187152007781668706
105 Sacchi A Gasparri A Gallo-Stampino C Toma S Curnis F Corti A Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor- α Clinical Cancer Research 2006 12 1 175 182 2-s2.0-31544436380 16397040 10.1158/1078-0432.CCR-05-1147
106 Ruoslahti E Bhatia SN Sailor MJ Targeting of drugs and nanoparticles to tumors Journal of Cell Biology 2010 188 6 759 768 2-s2.0-77949762340 20231381 10.1083/jcb.200910104 PMC2845077
107 Dickerson EB Akhtar N Steinberg H Enhancement of the antiangiogenic activity of interleukin-12 by peptide targeted delivery of the cytokine to α v β 3 integrin Molecular Cancer Research 2004 2 12 663 673 2-s2.0-12744274648 15634755
108 Gregorc V Santoro A Bennicelli E Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours British Journal of Cancer 2009 101 2 219 224 2-s2.0-67650638995 19568235 10.1038/sj.bjc.6605162 PMC2720203
109 Gregorc V De Braud FG De Pas TM Phase I study of NGR-hTNF, a selective vascular targeting agent, in combination with cisplatin in refractory solid tumors Clinical Cancer Research 2011 17 7 1964 1972 2-s2.0-79953306455 21307147 10.1158/1078-0432.CCR-10-1376
110 Santoro A Rimassa L Sobrero AF Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy European Journal of Cancer 2010 46 15 2746 2752 2-s2.0-77957197962 20708923 10.1016/j.ejca.2010.07.012
111 Li ZJ Cho CH Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery Journal of Translational Medicine 2012 10 supplement 1 p. S1 10.1186/1479-5876-10-S1-S1 PMC3445867 23046982
112 Soroceanu L Gillespie Y Khazaeli MB Sontheimer H Use of chlorotoxin for targeting of primary brain tumors Cancer Research 1998 58 21 4871 4879 2-s2.0-0032211350 9809993
113 Rosca EV Koskimaki JE Rivera CG Pandey NB Tamiz AP Popel AS Anti-angiogenic peptides for cancer therapeutics Current Pharmaceutical Biotechnology 2011 12 8 1101 1116 2-s2.0-79960006764 21470139 10.2174/138920111796117300 PMC3114256
114 Karagiannis ED Popel AS Novel anti-angiogenic peptides derived from ELR-containing CXC chemokines Journal of Cellular Biochemistry 2008 104 4 1356 1363 2-s2.0-46949106434 18307172 10.1002/jcb.21712
115 Kritzer JA Stephens OM Guarracino DA Reznika SK Schepartza A β -Peptides as inhibitors of protein-protein interactions Bioorganic & Medicinal Chemistry 2005 13 11 16 15582447 10.1016/j.bmc.2004.09.009 PMC2853017
116 Mochly-Rosen D Qvit N Peptide inhibitors of protein-protein interactions: from rational design to the clinic Chimica Oggi 2010 28 1 14 16 2-s2.0-77952979013
117 Eldar-Finkelman H Eisenstein M Peptide inhibitors targeting protein kinases Current Pharmaceutical Design 2009 15 21 2463 2470 2-s2.0-69249137908 19601843 10.2174/138161209788682253
118 Tonelli R Purgato S Camerin C Antigene peptide nucleic acid specifically inhibits MYCN expression in human neuroblastoma cells leading to cell growth inhibition and apoptosis Molecular Cancer Therapeutics 2005 4 5 779 786 2-s2.0-20044370996 15897242 10.1158/1535-7163.MCT-04-0213
119 Kakde D Jain D Shrivastava V Kakde R Patil AT Cancer therapeutics-opportunities, challenges and advances in drug delivery Journal of Applied Pharmaceutical Science 2011 1 9 1 10
120 Zheng L Wang Y Sheng J Antitumor peptides from marine organisms Marine Drugs 2011 9 1840 1859 22072999 10.3390/md9101840 PMC3210608
121 Cornelio DB Roesler R Schwartsmann G Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy Annals of Oncology 2007 18 9 1457 1466 2-s2.0-34548459014 17351255 10.1093/annonc/mdm058
122 Sotomayor S Muñoz-Moreno L Carmena MJ Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN-215) and a bombesin antagonist (RC-3095) International Journal of Cancer 2010 127 8 1813 1822 2-s2.0-77956996168 20099275 10.1002/ijc.25192
123 Smolarczyk R Cichoń T Graja K Hucz J Sochanik A Szala S Antitumor effect of RGD-4C-GG-D(KLAKLAK)2 peptide in mouse B16(F10) melanoma model Acta Biochimica Polonica 2006 53 4 801 805 2-s2.0-33846173911 17143339
124 Ellerby HM Arap W Ellerby LM Anti-cancer activity of targeted pro-apoptotic peptides Nature Medicine 1999 5 9 1032 1038 2-s2.0-0032819838 10.1038/12469 10470080
125 Walensky LD Kung AL Escher I Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix Science 2004 305 5689 1466 1470 2-s2.0-4444291734 15353804 10.1126/science.1099191 PMC1360987
126 Soto-Pantoja DR Menon J Gallagher PE Tallant EA Angiotensin-(1-7) inhibits tumor angiogenesis in human lung cancer xenografts with a reduction in vascular endothelial growth factor Molecular Cancer Therapeutics 2009 8 6 1676 1683 2-s2.0-67649366366 19509262 10.1158/1535-7163.MCT-09-0161 PMC3314264
127 Alghisi GC Ponsonnet L Rüegg C The integrin antagonist cilengitide activates α V β 3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells PLoS One 2009 4 2 2-s2.0-61849164535 e4449 10.1371/journal.pone.0004449 PMC2636874 19212436
128 Hariharan S Gustafson D Holden S Assessment of the biological and pharmacological effects of the α v β 3 and α v β 5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors Annals of Oncology 2007 18 8 1400 1407 2-s2.0-34548175694 17693653 10.1093/annonc/mdm140
129 Reardon DA Fink KL Mikkelsen T Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme Journal of Clinical Oncology 2008 26 34 5610 5617 2-s2.0-57149108506 18981465 10.1200/JCO.2008.16.7510
130 Park K Kim YS Lee GY Tumor endothelial cell targeted cyclic RGD-modified heparin derivative: inhibition of angiogenesis and tumor growth Pharmaceutical Research 2008 25 12 2786 2798 2-s2.0-57149126267 18581207 10.1007/s11095-008-9643-y
131 Khalili P Arakelian A Chen G A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo Molecular Cancer Therapeutics 2006 5 9 2271 2280 2-s2.0-33749577839 16985061 10.1158/1535-7163.MCT-06-0100
132 Noy A Scadden DT Lee J Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi’s sarcoma in a phase III trial, but demonstrates sustained, potent effect of highly active antiretroviral therapy: from the AIDS malignancy consortium and IM862 study team Journal of Clinical Oncology 2005 23 5 990 998 2-s2.0-14644445181 15598977 10.1200/JCO.2005.11.043
133 Deplanque G Madhusudan S Jones PH Phase II trial of the antiangiogenic agent IM862 in metastatic renal cell carcinoma British Journal of Cancer 2004 91 9 1645 1650 2-s2.0-9144235680 15354209 10.1038/sj.bjc.6602126 PMC2409952
134 Stangelberger A Schally AV Djavan B New treatment approaches for prostate cancer based on peptide analogues European Urology 2008 53 5 890 900 2-s2.0-41149086832 18201818 10.1016/j.eururo.2007.12.021
135 Cescato R Maina T Nock B Bombesin receptor antagonists may be preferable to agonists for tumor targeting Journal of Nuclear Medicine 2008 49 2 318 326 2-s2.0-38949198118 18199616 10.2967/jnumed.107.045054
136 Bajo AM Schally AV Krupa M Hebert F Groot K Szepeshazi K Bombesin antagonists inhibit growth of MDA-MB-435 estrogen-independent breast cancers and decrease the expression of the ErbB-2/HER-2 oncoprotein and c-jun and c-fos oncogenes Proceedings of the National Academy of Sciences of the United States of America 2002 99 6 3836 3841 2-s2.0-0037133576 11891317 10.1073/pnas.052715299 PMC122610
137 Cai RZ Qin Y Ertl T Schally AV New pseudononapeptide bombesin antagonists with C-terminal LeuΨ(CH2N)Tac-NH2 show high binding affinity to bombesin/GRP receptors on CFPAC-1 human pancreatic cancer cells International Journal of Oncology 1995 6 6 1165 1172 2-s2.0-0029025541 21556653 10.3892/ijo.6.6.1165
138 Hruby VJ Designing peptide receptor agonists and antagonists Nature Reviews Drug Discovery 2002 1 847 858 12415245 10.1038/nrd939
139 Letsch M Schally AV Busto R Bajo AM Varga JL Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers Proceedings of the National Academy of Sciences of the United States of America 2003 100 3 1250 1255 2-s2.0-0037417815 12538852 10.1073/pnas.0337496100 PMC298759
140 Hohla F Buchholz S Schally AV GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells Cell Cycle 2009 8 19 3149 3156 2-s2.0-70349916272 19755849 10.4161/cc.8.19.9698
141 Cardinale D Guaitoli G Tondi D Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase Proceedings of the National Academy of Sciences 2011 108 34 542 549 10.1073/pnas.1104829108 PMC3161595 21795601
142 Gaviglio L Gross A Metzler-Nolte N Ravera M Synthesis and in vitro cytotoxicity of cis, cis, trans-diamminedichloridodisuccinatoplatinum(IV)-peptide bioconjugates Metallomics 2012 4 3 260 266 22310724 10.1039/c2mt00171c
143 Mai JC Mi Z Kim SH Ng B Robbins PD A proapoptotic peptide for the treatment of solid tumors Cancer Research 2001 61 21 7709 7712 2-s2.0-0035503496 11691780
144 Laakkonen P Åkerman ME Biliran H Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells Proceedings of the National Academy of Sciences of the United States of America 2004 101 25 9381 9386 2-s2.0-3042687629 15197262 10.1073/pnas.0403317101 PMC438985
145 Nawrocki ST Carew JS Pino MS Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis Cancer Research 2005 65 24 11658 11666 16357177 10.1158/0008-5472.CAN-05-2370
146 Chen D Frezza M Schmitt S Kanwar J Dou QP Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives Current Cancer Drug Targets 2011 11 3 239 253 2-s2.0-79951702955 21247388 10.2174/156800911794519752 PMC3306611
147 Meyers PA Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma Expert Review of Anticancer Therapy 2009 9 8 1035 1049 2-s2.0-70350678863 19671023 10.1586/era.09.69
148 Inohara N Ogura Y Fontalba A Host recognition of bacterial muramyl dipeptide mediated through NOD2: implications for Crohn’s disease Journal of Biological Chemistry 2003 278 8 5509 5512 2-s2.0-0037458665 12514169 10.1074/jbc.C200673200
149 Francisco JA Cerveny CG Meyer DL cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity Blood 2003 102 4 1458 1465 2-s2.0-0042738861 12714494 10.1182/blood-2003-01-0039
150 Senter PD The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma Nature Biotechnology 2012 30 631 637 10.1038/nbt.2289 22781692
151 Foy KC Miller MJ Moldovan N Carson III WE Kaumaya PT Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo OncoImmunology 2012 1 1048 1060 23170253 10.4161/onci.20708 PMC3494619
152 Stupp R Hegi ME Neyns B Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma Journal of Clinical Oncology 2010 28 16 2712 2718 2-s2.0-77954924659 20439646 10.1200/JCO.2009.26.6650
153 Retter AS Figg WD Dahut WL The combination of antiangiogenic and cytotoxic agents in the treatment of prostate cancer Clinical Prostate Cancer 2003 2 3 153 159 2-s2.0-0348225315 15040858 10.3816/cgc.2003.n.023
154 Andersen MH Junker N Ellebaek E Svane IM Straten PT Therapeutic cancer vaccines in combination with conventional therapy Journal of Biomedicine and Biotechnology 2010 2010 10 pages 237623 10.1155/2010/237623 PMC2896846 20617155
155 Rick FG Buchholz S Schally AV Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers Cell Cycle 2012 11 13 2518 2525 22751419 10.4161/cc.20900 PMC3404878