Enhancement of antitumor activity of the oxazaphosphorine cytostatic SUM-IAP by N-methylformamide

SUM-IAP has been developed with the aim to optimize therapeutic response and minimize toxic reactions of oxazaphosphorine cytostatics. In therapy tests in mice, the primary tumor was successfully eradicated, but animals died due to formation of lethal metastases. We supposed that high activities of SUM-IAP detoxifying enzymes caused metastasis formation in the liver. Therefore, therapy tests with SUM-IAP in combination with cisplatin and N-methylformamide (NMF), which were not detoxified in the liver, were carried out. Antitumor activity was assayed in female CD2F1 mice with advanced subcutaneously growing P388 mice leukemia cells. The results of the therapy tests with SUM-IAP plus cisplatin were as expected: No formation of metastases and long-time survival of more than 100 days were observed; however, the toxicity was increased as measured by decrease in body weight and the number in leukocytes. The results of the tests in combination with NMF were surprising: Applying only half the dose of SUM-IAP used in the experiments with cisplatin, no metastases were found and long-time survivors did not show signs of additional toxicity. NMF strongly enhances the antitumor activity of the oxazaphosphorine cytostatic SUM-IAP in mice with subcutaneously growing P388 mice leukemia cells by an unknown mechanism of action.