Antitumoral activity of the oxazaphosphorine derivative, mafosfamide-cyclohexylamine salt (ASTA 7557) on a murine ovarian reticular cell sarcoma and its subline resistant to cyclophosphamide

Abstract

The antitumor activity of mafosfamide (MFA), and its parent compound cyclophosphamide (CTX), was investigated against an ovarian reticular cell sarcoma growing i.m. in C57BI/6 mice (M5), which is very sensitive to CTX, and against a subline of this tumor (R16) resistant to CTX. MFA is the prototype of a class of oxazaphosphorines which do not require metabolic activation since under physiologic conditions they undergo rapid spontaneous hydrolyzation to the activated 4-hydroxyoxazaphosphorine and retain a spectrum of activity very similar to the parent compound. After a single dose (300 mg/kg X 1) or repeated low doses (100 mg/kg X 6) the antitumoral activity of MFA on the M5 tumor appeared comparable to or only slightly lower than CTX; the highest T/C value for median survival times was 167% in MFA-treated mice vs. 176% in the CTX group. MFA showed no activity against the R16 subline, thus indicating cross-resistance between the two drugs. Marked thickening of the glissonian capsule with compression of the lobular area of the liver, observed on i.p. administration of MFA, did not result in histopathologic abnormalities of the hepatic parenchyma. The therapeutic efficacy of MFA was similar with i.p. and the i.v. route. MFA may represent a good candidate to replace CTX in cases in which a compound acting per se, and not through metabolites, is preferred.