The pyrimido-pyrimidine derivatives RA233 and RX-RA85 affect cell cycle distribution of two murine tumour cell lines

Abstract

The pyrimido-pyrimidine derivatives RA233 and RX-RA85, which are potent inhibitors of platelet and tumour phosphodiesterases, were developed as antitumour agents. Clinical as well as animal studies suggest a tumour type specific, although moderate, antitumour activity for RA233. In our search for more potent congeners of RA233, we found that RX-RA85 was cytotoxic for cultured B16 melanoma and Lewis lung carcinoma cells at drug concentrations above 4 micrograms/ml whereas RA233 concentrations up to 400 micrograms/ml were tolerated. When tested for their effects on cell cycle distribution, RX-RA85 was 100-fold more potent than RA233 in producing an increase in the proportion of cells in S and G2 + M phase in 3LL cells. Progression of 3LL cells through the cell cycle was delayed for 5 h by RA233 treatment, whereas RX-RA85 was ineffective. In contrast, B16 cells responded poorly to either drug. The effects of both compounds were not only tumour cell specific but also dependent on the stage of tumour cell growth (drugs added to synchronously vs. asynchronously growing cultures). In the case of RX-RA85, the potency to affect tumour cell cycle distribution was highly dependent on tumour cell number, making the potential of this drug as an antitumour agent somewhat limited.