A mathematical theory of the transcription repression (TR) therapy of cancer - whether and how it may work.

Transcription repression (TR) therapy of cancer has been widely discussed. Here, TR refers to global repression of transcription rather than specific targeting of cancer-causing genes such as MYC. TR drugs inhibit transcription by binding to the transcribed DNA or to RNA polymerase; for example, actinomycin D has been extensively used in research and therapy to shut down transcription globally [1-7]. As proliferating cells demand a high rate of transcription, restricting transcript production could be effective in slowing down cell proliferation. However, TR also deprives other less proliferative cells of new transcripts, thus leading to substantial toxicity [1, 8, 9]. We now develop a mathematical theory to exploit the greater demand for transcription in highly proliferating cells. A new strategy, referred to as the TRR (transcript repression-recovery) model, would insert a recovery phase to allow the more slowly proliferating cells to recover. It is most effective to have strong blocking for a short period (a few hours) followed by a longer recovery phase in each cell cycle. Hence, TRR can potentially achieve selective killing of cells based on their global transcription needs but precise fine-tuning is necessary.