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The antitumour effect and toxicity of cis-platinum and N-methylformamide in combination

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Summary

N-Methylformamide (NMF), currently under-going phase II clinical evaluation for the treatment of cancer, and the established antitumour agent cis-platinum (CDDP) have nonoverlapping toxicities, with the exception of gastrointestinal side effects. The major target organs for the toxicities of the compounds are the liver (NMF) and the kidney (CDDP). Furthermore, NMF is nonleukopenic. In view of this, and of recent evidence that NMF enhances the cytotoxic effect of CDDP in vitro the activity of NMF and CDDP against the M5076 sarcoma implanted in mice was investigated, together with the various toxicities in mice and rats. The antitumour effect of NMF in combination with CDDP was additive, but NMF did not alter the leukopenia produced by CDDP in the tumour-bearing mice. CDDP produced only a minimal increase in the hepatotoxicity of NMF in mice, and NMF did not augment the nephrotoxicity of CDDP in rats (except for a small effect on calcium excretion). The results support suggestions that clinical evaluation of combination chemotherapy with NMF and CDDP is warranted.

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References

  1. 1.

    Blachley JD, Hill JB (1981) Renal and electrolyte disturbances associated with cisplatin. Ann Intern Med 95:628

  2. 2.

    Buamah PK, Howell A, Whitby H, Harpur ES, Gescher A (1982) Assessment of renal function during high dose cis-platinum therapy in patients with ovarian carcinoma. Cancer Chemother Pharmacol 8:281

  3. 3.

    Clarke CA, Phillips FS, Sternberg RK, Barclay RK, Stock CC (1953) Effects of N-methylformamide and related compounds in sarcoma 180. Proc Soc Exp Biol Med 84:203

  4. 4.

    Collins SJ, Ruscetti FW, Gallagher RE, Gallo RC (1978) Terminal differentiation of human promyelocytic leukaemia cells induced by dimethyl sulphoxide and other polar solvents. Proc Natl Acad Sci USA 75:2458

  5. 5.

    Davis S, Kessler W, Haddad BM, Maesaka JK (1980) Acute renal tubular dysfunction following cis-dichlorodiammine-platinum therapy. J Med 11:133

  6. 6.

    Dentino M, Luft FC, Yum MN, Williams SD, Einhorn LH (1978) Long term effect of cis-diamminedichloride platinum (CDDP) on renal function and structure in man. Cancer 41: 1274

  7. 7.

    Dexter DL, Spremulli EN, Matook GM, Diamond E, Calabresi P (1982) Inhibition of the growth of human colon cancer xenografts by polar solvents. Cancer Res 42:5018

  8. 8.

    Dexter DL, De Fusco DJ, McCarthy K, Calabresi P (1983) Polar solvents increase the sensitivity of cultured human colon cancer cells to cisplatinum and mitomycin-C. Proc Am Assoc Cancer Res 24:267

  9. 9.

    Dexter DL, Lee ES, Bliven S, Glicksman AS, Leith JT (1984) Enhancement by N-methylformamide of the effects of photon irradiation on a human colon cancer xenograft. Proc Am Assoc Cancer Res 25:321

  10. 10.

    Jones BR, Bhalla RB, Mladek J, Kaleya RN, Gralla RJ, Alcock NW, Schwartz MK, Young CW, Reidenberg MM (1980) Comparison of methods of evaluating nephrotoxicity of cis-platinum. Clin Pharmacol Ther 27:557

  11. 11.

    Kachmar JF, Moss DW (1976) Enzymes: In: Teitz NW (ed) Fundamentals of clinical chemistry. Saunders, Philadelphia, p 672

  12. 12.

    Langdon SP, Hickman JA, Gescher A, Stevens MFG, Chubb D, Vickers LM (1983) N-Methylformamide (NSC 3051): a potential candidate for combination chemotherapy. Eur J Cancer Clin Oncol 21:745

  13. 13.

    Langdon SP, Gescher A, Hickman JA, Stevens MFG (1984) The chemosensitivity of a new experimental model — the M5076 reticulum cell sarcoma. Eur J Cancer Clin Oncol 20: 699

  14. 14.

    Leathwood PD, Plummer DT (1969) Enzymes in rat urine: I. A metabolism cage for the complete separation of urine and faeces. Enzymologica 37:240

  15. 15.

    Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99

  16. 16.

    Lowry OH, Rosenbrough NJ, Farr Al, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265

  17. 17.

    Luft FC, Patel V (1979) Lysosomal acid hydrolases as urinary markers of aminoglycoside nephrotoxicity in the rat. In: Fillastre J-P (ed) Colloque international — Nephrotoxicity. Interactions of drugs with membrane systems, mitochondria and lysosomes. Masson, New York, p 127

  18. 18.

    McVie JG, ten Bokkel Huinink WW, Simonetti G, Dubbelman R (1984) Phase I trial of N-methylformamide. Cancer Treat Rep 68:607

  19. 19.

    Meyers WPL, Karnofsky D, Burchenal JH (1956) The hepatotoxic action of N-methylformamide in man. Cancer 9:949

  20. 20.

    Mondorf AW, Kinne R, Scherberich JE, Falkenberg F (1972) Isolierung enzymatische und immunologische Characterisierung einer Plasmamembranfraktion vom proximalen Tubulus der menschlichen Niere. Clin Chim Acta 37:25

  21. 21.

    Newman KN, Meeks RG, Frick S (1981) Phase I report of task I preclinical intravenous toxicity study of N-methylformamide (NSC 3051) in CDF1 mice and beagle dogs. Southern Research Institute, Birmingham, Ala

  22. 22.

    Nitschke R (1981) Renal and electrolyte disturbances associated with cisplatin. Ann Intern Med 95:628

  23. 23.

    Rose CI, Henderson AR (1975) Reaction rate assay of serum sorbitol dehydrogenase activity at 37°C. Clin Chem 21:1619

  24. 24.

    Schilsky RL, Anderson T (1979) Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin. Ann Intern Med 90:929

  25. 25.

    Ward JM, Young DM, Fauvie KA, Wolpert MK, Davis R, Guarino AM (1976) Comparative nephrotoxicity of platinum cancer chemotherapeutic agents. Cancer Treat Rep 60:1675

  26. 26.

    Whitby H, Chahwala SB, Gescher A (1984a) The effect of N-methylformamide (NSC 3051) on the uptake of calcium by mouse liver microsomes and mitochondria. Proc Am Assoc Cancer Res 25:380

  27. 27.

    Whitby H, Gescher A, Levy L (1984b) An investigation of the mechanism of hepatotoxicity of the antitumor agent N-methylformamide in mice. Biochem Pharmacol 33:295

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Correspondence to Ernest S. Harpur.

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Harpur, E.S., Langdon, S.P., Fathalla, S.A.K. et al. The antitumour effect and toxicity of cis-platinum and N-methylformamide in combination. Cancer Chemother. Pharmacol. 16, 139–147 (1986). https://doi.org/10.1007/BF00256164

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Keywords

  • Sarcoma
  • Clinical Evaluation
  • Cytotoxic Effect
  • Target Organ
  • CDDP