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. 1983 Jan;47(1):15–26. doi: 10.1038/bjc.1983.2

Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumours comparable to cyclophosphamide.

R F Struck, D J Dykes, T H Corbett, W J Suling, M W Trader
PMCID: PMC2011256  PMID: 6821629

Abstract

Isophosphoramide mustard was synthesized and was found to demonstrate activity essentially comparable to cyclophosphamide and ifosfamide against L1210 and P388 leukaemia. Lewis lung carcinoma, mammary adenocarcinoma 16/C, ovarian sarcoma M5076, and colon tumour 6A, in mice and Yoshida ascitic sarcoma in rats. At doses less than, or equivalent to, the LD10, isophosphoramide mustard retained high activity against cyclophosphamide-resistant L1210 and P388 leukaemias, but was less active against intracerebrally-implanted P388 leukaemia while cyclophosphamide produced a 4 log10 tumour cell reduction. It was also less active (one log10 lower cell kill) than cyclophosphamide against the B16 melonoma. Metabolism studies on ifosfamide in mice identified isophosphoramide mustard in blood. In addition, unchanged drug, carboxyifosfamide, 4-ketoifosfamide, dechloroethyl cyclophosphamide, dechloroethylifosfamide, and alcoifosfamide were identified. The latter 4 metabolites were also identified in urine from an ifosfamide-treated dog. In a simulated in vitro pharmacokinetic experiment against L1210 leukaemia in which drugs were incubated at various concentrations for various times, both 4-hydroxycyclophosphamide and isophosphoramide mustard exhibited significant cytoxicity at concentration times time values of 100-1000 micrograms X min ml-1, while acrolein was significantly cytotoxic at 10 micrograms X min ml-1. Treatment of mice with drug followed by L1210 cells demonstrated a shorter duration of effective levels of cytotoxic activity for isophosphoramide mustard and phosphoramide mustard in comparison with cyclophosphamide and ifosfamide. Isophosphoramide mustard and 2-chloroethylamine, a potential hydrolysis product of isophosphoramide mustard and carboxyifosfamide, were less mutagenic in the standard Ames test than the 2 corresponding metabolites of cyclophosphamide [phosphoramide mustard and bis(2-chloroethyl)amine].

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Selected References

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  1. Alarcon R. A., Meienhofer J., Atherton E. Isophosphamide as a new acrolein-producing antineoplastic isomer of cyclophosphamide. Cancer Res. 1972 Nov;32(11):2519–2523. [PubMed] [Google Scholar]
  2. Alberts D. S., Peng Y. M., Chen H. S., Struck R. F. Effect of phenobarbital on plasma levels of cyclophosphamide and its metabolites in the mouse. Br J Cancer. 1978 Aug;38(2):316–324. doi: 10.1038/bjc.1978.204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ames B. N., Mccann J., Yamasaki E. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat Res. 1975 Dec;31(6):347–364. doi: 10.1016/0165-1161(75)90046-1. [DOI] [PubMed] [Google Scholar]
  4. Bakke J. E., Feil V. J., Fjelstul C. E., Thacker E. J. Metabolism of cyclophosphamide by sheep. J Agric Food Chem. 1972 Mar-Apr;20(2):384–388. doi: 10.1021/jf60180a054. [DOI] [PubMed] [Google Scholar]
  5. Brock N. Nouveaux esters phosphamidés de moutarde azotée et leur activité cytostatique. Laval Med. 1968 Oct;39(8):696–701. [PubMed] [Google Scholar]
  6. Brock N., Stekar J., Pohl J., Niemeyer U., Scheffler G. Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Arzneimittelforschung. 1979;29(4):659–661. [PubMed] [Google Scholar]
  7. Bryant B. M., Jarman M., Ford H. T., Smith I. E. Prevention of isophosphamide-induced urothelial toxicity with 2-mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet. 1980 Sep 27;2(8196):657–659. doi: 10.1016/s0140-6736(80)92703-8. [DOI] [PubMed] [Google Scholar]
  8. Claussen U., Hellmann W., Pache G. The embryotoxicity of the cyclophosphamide metabolite acrolein in rabbits, tested in vivo by i.v. injection and by the yolk-sac method. Arzneimittelforschung. 1980;30(12):2080–2083. [PubMed] [Google Scholar]
  9. Colvin M., Brundrett R. B., Kan M. N., Jardine I., Fenselau C. Alkylating properties of phosphoramide mustard. Cancer Res. 1976 Mar;36(3):1121–1126. [PubMed] [Google Scholar]
  10. Corbett T. H., Griswold D. P., Jr, Roberts B. J., Peckham J. C., Schabel F. M., Jr Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas. Cancer. 1977 Nov;40(5 Suppl):2660–2680. doi: 10.1002/1097-0142(197711)40:5+<2660::aid-cncr2820400940>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  11. Corbett T. H., Griswold D. P., Jr, Wolpert M. K., Venditti J. M., Schabel F. M., Jr Design and evaluation of combination chemotherapy trials in experimental animal tumor systems. Cancer Treat Rep. 1979 May;63(5):799–801. [PubMed] [Google Scholar]
  12. Cox P. J. Cyclophosphamide cystitis--identification of acrolein as the causative agent. Biochem Pharmacol. 1979 Jul 1;28(13):2045–2049. doi: 10.1016/0006-2952(79)90222-3. [DOI] [PubMed] [Google Scholar]
  13. Cox P. J., Phillips B. J., Thomas P. The enzymatic basis of the selective action of cyclophosphamide. Cancer Res. 1975 Dec;35(12):3755–3761. [PubMed] [Google Scholar]
  14. Domeyer B. E., Sladek N. E. Kinetics of cyclophosphamide biotransformation in vivo. Cancer Res. 1980 Jan;40(1):174–180. [PubMed] [Google Scholar]
  15. Friedman O. M., Wodinsky I., Myles A. Cyclophosphamide (NSC-26271)-related phosphoramide mustards- recent advances and historical perspective. Cancer Treat Rep. 1976 Apr;60(4):337–346. [PubMed] [Google Scholar]
  16. Hill D. L., Laster W. R., Jr, Kirk M. C., el-Dareer S., Struck R. F. Metabolism of iphosphamide (2-(2-chloroethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide) and production of a toxic iphosphamide metabolite. Cancer Res. 1973 May;33(5):1016–1022. [PubMed] [Google Scholar]
  17. Jardine I., Fenselau C., Appler M., Kan M. N., Brundrett R. B., Colvin M. Quantitation by gas chromatography-chemical ionization mass spectrometry of cyclophosphamide, phosphoramide mustard, and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy. Cancer Res. 1978 Feb;38(2):408–415. [PubMed] [Google Scholar]
  18. Lenssen U., Hohorst H. J. Zur Frage der Permeabilität von N,N-Bis(2-chloräthyl)-phosphorsäurediamid in Tumorzellen. J Cancer Res Clin Oncol. 1979 Feb 19;93(2):161–164. doi: 10.1007/BF00406573. [DOI] [PubMed] [Google Scholar]
  19. Marinello A. J., Gurtoo H. L., Struck R. F., Paul B. Denaturation of cytochrome P-450 by cyclophosphamide metabolites. Biochem Biophys Res Commun. 1978 Aug 29;83(4):1347–1353. doi: 10.1016/0006-291x(78)91369-4. [DOI] [PubMed] [Google Scholar]
  20. Morgan L. R., Posey L. E., Rainey J., Bickers J., Ryan D., Vial R., Hull E. W. Ifosfamide: a weekly dose fractionated schedule in bronchogenic carcinoma. Cancer Treat Rep. 1981 Jul-Aug;65(7-8):693–695. [PubMed] [Google Scholar]
  21. Norpoth K. Studies on the metabolism of isopnosphamide (NSC-109724) in man. Cancer Treat Rep. 1976 Apr;60(4):437–443. [PubMed] [Google Scholar]
  22. Ramonas L. M., Erickson L. C., Klesse W., Kohn K. W., Zaharko D. S. Differential cytotoxicity and DNA cross-linking produced by polymeric and monomeric activated analogues of cyclophosphamide in mouse L1210 leukemia cells. Mol Pharmacol. 1981 Mar;19(2):331–336. [PubMed] [Google Scholar]
  23. Rauen H. M., Schriewer H. Alkylans-Alkylandum-Reaktionen. 4. 2-Chloräthylamin und -Phosphamidverbindungen als Alkylantien. Arzneimittelforschung. 1971 Apr;21(4):518–524. [PubMed] [Google Scholar]
  24. Scheef W., Klein H. O., Brock N., Burkert H., Günther U., Hoefer-Janker H., Mitrenga D., Schnitker J., Voigtmann R. Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results. Cancer Treat Rep. 1979 Mar;63(3):501–505. [PubMed] [Google Scholar]
  25. Sladek N. E. Cytotoxic activity of alkylating agents in the presence of centrophenoxine and its hydrolysis products. J Pharmacol Exp Ther. 1977 Dec;203(3):630–639. [PubMed] [Google Scholar]
  26. Struck R. F., Kirk M. C., Witt M. H., Laster W. R., Jr Isolation and mass spectral identification of blood metabolites of cyclophosphamide: evidence for phosphoramide mustard as the biologically active metabolite. Biomed Mass Spectrom. 1975 Feb;2(1):46–52. doi: 10.1002/bms.1200020109. [DOI] [PubMed] [Google Scholar]
  27. Takamizawa A., Matsumoto S., Iwata T., Tochino Y., Katagiri K. Synthesis and metabolic behavior of the suggested active species of isophosphamide having cytostatic activity. J Med Chem. 1974 Nov;17(11):1237–1239. doi: 10.1021/jm00257a024. [DOI] [PubMed] [Google Scholar]

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