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Direct Effects of the Pyrimido-Pyrimidine Derivative RA 233 (Rapenton) on Rat 13762NF Mammary Tumor Cell Clones in Vitro

Department of Tumor Biology, The University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030 [R. B. L., G. L. N.], and the Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas 77030 [T. J. G., R. W. B.]

Studies with the pyrimido-pyrimidine analogue RA 233 (Rapenton) suggest that its antimetastatic action may not be mediated entirely by inhibition of platelet function. Little is known about its direct effects on tumor cells. We investigated the in vitro effects of RA 233 on clones MTLn3 and MTC of differing metastatic potentials, isolated from the 13762NF rat mammary adenocarcinoma. The results indicated that RA 233 is cytostatic (EC₅₀ of 140 µM and 180 µM for MTLn3 and MTC cells, respectively) rather than cytotoxic by determining changes in viable cell number, thymidine uptake, and incorporation of thymidine and methionine. In both clones RA 233 inhibited cAMP-dependent phosphodiesterase activity and affected cAMP accumulation in intact cells. In contrast, clonal heterogeneity in drug-induced morphological changes, such as vacuole formation and altered organization of cytoskeletal structures, as well as increased tumor cell growth at 50 µM RA 233 was observed between clones MTLn3 and MTC. These data could explain the conflicting results obtained with RA 233 when evaluated as an antimetastatic agent.

¹ Supported by NIH Grant RO1-AM26943.

² To whom requests for reprints should be addressed, at University of Texas Cancer Center, M. D. Anderson Hospital, Department of Tumor Biology, Box 108, 1515 Holcombe Boulevard, Houston, TX 77030. Supported by NIH Grant RO1-CA28844 P30-CA16672 and grants from Dr. Karl Thomae GmbH and the Susan G. Koman Foundation.

Received 7/21/86. Revised 12/31/86. Accepted 1/ 8/87.