The pyrimido-pyrimidine derivatives RA 233 and RX-RA 85 affect growth and cytoskeletal organization of rat mammary adenocarcinoma cells.

The pyrimido-pyrimidine derivatives RA 233 and RX-RA 85, which are potent inhibitors of platelet and tumor phosphodiesterase, were developed as antitumor agents. When tested by us, these drugs were cytostatic at low concentrations and produced dramatic changes in cell shape and organization of cytoskeletal structures in cultured MTF7 cells derived from the rat 13762NF mammary adenocarcinoma. At high concentrations (up to 600 micrograms/ml) RA 233 was cytostatic but not cytotoxic to MTF7 cells during a 24 hr incubation in vitro, whereas RX-RA 85 was cytotoxic at concentrations above 4 micrograms/ml. These drugs caused MTF7 cells to elongate and form numerous vacuoles, which surrounded the cell nucleus. Treatment of MTF7 cells with RA 233 or RX-RA 85 enhanced microtubular organization concomitant with a decrease in microfilament organization. In contrast, treatment of MTF7 cells with 1 mM dibutyryl cAMP resulted in an enhanced organization of microtubules but had no effect on microfilament organization. Previous studies suggested that RA 233 and RX-RA 85 increase cAMP levels in 2 other cell clones of rat 13762NF mammary adenocarcinoma by inhibiting phosphodiesterases. However, additional sites of drug action should also be considered based on the effects of these drugs on microfilament systems and cell vacuoles.