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Journal of Cancer Research and Clinical Oncology

, Volume 142, Issue 6, pp 1183–1189 | Cite as

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

  • G. VoelckerEmail author
Original Article – Cancer Research

Abstract

Purpose

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.

Method

Antitumor activity was assayed in female CD2F1 mice with advanced subcutaneously growing P388 mice leukemia cells.

Result

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.

Conclusion

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.

Keywords

Oxazaphosphorine cytostatics SUM-IAP N-methylformamide Cisplatin 

Notes

Acknowledgments

For critical review and proof reading of the manuscript, I thank Prof. Frank Nürnberger and Prof. Stefan Müller Goethe University Frankfurt, Medical School, Frankfurt am Main, Germany.

Funding

This study was funded by the Bundesministerium für Forschung und Technologie.

Compliance with ethical standards

Conflict of interest

The author declares no conflict of interest.

Ethical approval

All applicable international, national and institutional guidelines for the care and use of animals were followed.

References

  1. Bielicki L, Voelcker G, Hohorst HJ (1983) Enzymatic toxicogenation of activated cyclophosphamide by 3′–5′ exonucleases. J Cancer Res Clin Oncol 105:27–29CrossRefPubMedGoogle Scholar
  2. Bielicki L, Voelcker G, Hohorst HJ (1984) Activated cyclophosphamide: an enzyme- mechanism-based suicide inactivator of DNA polymerase/3′–5′ exonuclease. J Cancer Res Clin Oncol 107:195–198CrossRefPubMedGoogle Scholar
  3. Chatterjee D, Mendelsohn A, Shank PR, Savarese TM (1989) Reversible Suppression of c-myc Expression in a human colon carcinoma line by the anticancer agent N-methylformamide. Cancer Res 49:3910–3916PubMedGoogle Scholar
  4. Clarke CA, Philips SF, Sternber SS (1953) Effects of N-methylformamide and related compounds in sarcoma 180. Proc Soc Exp Biol Med 84:203–207CrossRefPubMedGoogle Scholar
  5. Codeiro RF, Savarese TM (1986) Role of glutathione depletion in the mechanism of action of N-methylforamide and N, N-dimethylformamide in a cultured human colon carcinoma cell line. Cancer Res 46:1297–1305Google Scholar
  6. Gescher A, Gibson NW, Hickman JA, Langdon SP, Ross D, Atassi G (1982) N-methylformamide: antitumor activity and metabolism in mice. Br J Cancer 45:483–485CrossRefGoogle Scholar
  7. Hohorst HJ, Bielicki L, Mülller K, Voelcker G (1988) Low toxicity cancer chemotherapy by suicide inactivation of DANN polymerase holoenzyme: first results with new thiazolidinyl- and perhydrothiazinyl-ethyl-N-mustard-phosphamide-esters. J Cancer Res Clin Oncol 114:309–311CrossRefPubMedGoogle Scholar
  8. Iwakawa M, Tofilon PJ, Hunter N, Stephens LC, Milas L (1987) Antitumor and antimetastatic activity of the differentiating agent N-methylformamide in murine tumor systems. clin Exp Metastasis 5(4):289–300CrossRefPubMedGoogle Scholar
  9. Kalyani D, Jyothi K, Sivaprakasam C, Nachiappan V (2014) Spectroscopic and molecular modeling studies on interactions of N-methylformamide with superoxide dismutase. Mol Biomol Spectrosc 124:148–152CrossRefGoogle Scholar
  10. Malorny W, Meschini S, Arancia G (1992) Cytoskeleton-dependent surface blebbing induced by the polar solvent N-methylforamide. Exp Mol Pathol 57:85–104CrossRefGoogle Scholar
  11. Meyers WPL, Karnowsky DA, Burchenal JH (1956) The hepatotoxic action of N-methylformamide in man. Cancer 9:949–954CrossRefGoogle Scholar
  12. O´Dwyer PJ, Frcsi MD, McCabe DP, Sickle-Santanello BJ, Woltering EA, Clausen K, Martin EW (1988) Use of polar solvents in chemoprevention of 1,2-dimethylhydrazin-induced colon cancer. Cancer 62:944–948CrossRefGoogle Scholar
  13. Pagnotta E, Calonghi N, Boga C, Masotti L (2005) N-methylforamide and 9-hydroxystearic acid with different modes of action I, n colon cancer cells. Anticancer Drugs 17(5):521–526CrossRefGoogle Scholar
  14. Tofilon PJ, Vines CM, Milas L (1987) The effect of N-methylformamide on artificial and spontaneous metastases from a murine hepatocarcinoma. Br J Cancer 55:239–243CrossRefPubMedPubMedCentralGoogle Scholar
  15. Voelcker G, Hohorst HJ (1998) Structure/activity studies with thiazolidinyl- and perhydrthiazinyl phosphamide esters. J Cancer Res Clin Oncol 124:297–300CrossRefPubMedGoogle Scholar
  16. Voelcker G, Bielicki L, Hohorst HJ (1981) Evidence for enzymatic toxification of activated Cyclophosphamide (4-hydroxycyclophosphamide). J Cancer Res Clin Oncol 99A:58–59Google Scholar
  17. Watanabe K, Shibuya S, Koyama H, Ozawa Y, Toda T, Yokote K, Shimizu T (2013) Sod1 loss induces intrinsic superoxide accumulation leading to p53-mediated growth arrest and apoptosis. Int J Mol Sci 14:10998–11010CrossRefPubMedPubMedCentralGoogle Scholar
  18. Wood AC, Elvin P, Hickman JA (1995) Induction of apoptosis by anti cancer drugs with disperate modes of action: kinetics of cell death and changes in c-myc expression. Br J Cancer 71:937–941CrossRefPubMedPubMedCentralGoogle Scholar
  19. Zimmermann J, Bauer HH, Hohorst HJ, Voelcker G (2000) Synthesis of I-aldophosphamide-perydrothiazines. Arzneimittelforschung 50(9):843–847PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Institute of Biochemistry IIGoethe University Frankfurt Medical SchoolFrankfurtGermany

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