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Mechanism of Action of a New Antitumor Agent, Carbetimer¹

Department of Medical Oncology, LAC-USC Medical Center, Kenneth Norris Jr. Cancer Hospital and Research Institute [B. A.], Los Angeles, California 90033; and Monsanto Company [G. E. P.], St. Louis, Missouri 63167

Carbetimer, an intermediate molecular-weight-derivatized copolymer of maleic anhydride and ethylene, has been shown to possess significant antineoplastic activity in the stem cell assay. We have examined the antitumor activity of carbetimer in vivo and in vitro against HM5-Carb/S and M21, both primary human melanoma cell lines sensitive and resistant to carbetimer, respectively. The mechanism of action of carbetimer in HM5-Carb/S has been determined. Mice bearing palpable sensitive tumors were treated with 10% lethal doses of carbetimer (1500 mg/kg i.p.). The tumor nucleotide profile was determined 4 hours later. Uridine and cytidine nucleoside triphosphates were reduced by 36.6 and 58.2%, respectively. In a similar experiment using carbetimer-resistant tumor, there was no change in the tumor pool sizes of uridine and cytidine nucleoside triphosphate pools in carbetimer- or saline-treated animals. Following 24-h exposure of the cells to 1000 µM concentration of carbetimer, the carbetimer-sensitive cells were pulsed with [¹⁴C]uridine, cytidine, or thymidine for 30 min. Pyrimidine nucleotides, in particular triphosphates, were reduced significantly as compared to the salinetreated control. Similar treatment of carbetimer-resistant cells resulted in no change in the pool sizes of the nucleotides. [¹⁴C]Bicarbonate flux studies demonstrated that [¹⁴C]CO₂ conversion into UMP and CMP was increased 200 and 140% of control in the carbetimer-sensitive cells treated with 1000 µM carbetimer; however, a similar treatment of the resistant cells showed no change in the pool sizes of the nucleotide. Examination of pyrimidine salvage enzymes demonstrated that, in the sensitive cells, carbetimer treatment reduced the specific activity of uridine, cytidine, and thymidine kinase by 46, 37, and 60%. In a similar study using resistant cells, the specific activities were reduced 7 and 0%, respectively. In the restitution studies coincubation of carbetimer-sensitive cells with carbetimer and uridine resulted in essentially the reversal of carbetimer cytotoxicity. Thus, carbetimer inhibits the growth of the sensitive cells by inhibiting the uptake and metabolism of preformed nucleosides both in vivo and in vitro.

¹ Supported by Monsanto Company, St. Louis, MO.

² To whom requests for reprints should be addressed, at LAC-USC Medical Center, Room 10-440, 1200 North State Street, Los Angeles, CA 90033.

Received 3/ 4/86. Revised 7/22/86. Accepted 7/23/86.