rx-ra-85 and Lung-Neoplasms

The role of antiplatelet drugs in relation to their potential antimetastatic activities has been reviewed and the effects of two pyrimido-pyrimidine derivatives (RX-RA69 and RX-RA85) with strong antiplatelet activities investigated in metastasizing tumour models. The routes of administration and drug dosages were always chosen in such a way that good antiplatelet activities were obtained. RX-RA69 (20 mg/kg/day) given in the drinking water had no effect on spontaneous metastasis of Lewis lung carcinoma. RX-RA85 (20 mg/kg/day) did not influence spontaneous metastasis of B16 melanoma. On the other hand, giving RX-RA85 (8 mg/kg) daily i.p. to Lewis lung carcinoma bearing mice significantly increased the number of lung metastases but had no significant effect on primary tumour implant growth. Pretreating mice orally with 20 mg/kg RX-RA85 1 h before i.v. injection of B16 melanoma cells had no significant effect on lung colony number or distribution of extrapulmonary tumours while injecting the same dosage of RX-RA85 i.v. 1-2 h before tumour-cell injection decreased lung colony formation, but increased extrapulmonary tumour burden. This investigation like many others does not support the importance of platelets in metastasis formation.

Topics: Animals; Blood Platelets; Cyclic AMP; Humans; Lung Neoplasms; Melanoma; Mice; Mopidamol; Neoplasm Metastasis; Platelet Aggregation; Pyrimidines; Rats

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.

Topics: Animals; Cell Cycle; Cell Line; Flow Cytometry; Lung Neoplasms; Melanoma, Experimental; Mice; Mopidamol; Phosphodiesterase Inhibitors; Pyrimidines; Tumor Cells, Cultured