Evaluation of 3-(p-fluorophenyl)-l-alanyl-3-[m-bis(2-chloroethyl)aminophenyl]-l-alanyl-l-methionine ethyl ester HCl (PTT.119) against xenografts of human rhabdomyosarcoma

Summary PTT.119 [p-F-phe-m-bis(2-chloroethyl)amino-l-phe-met ethoxy HCl], a synthetic tripeptide mustard, was evaluated for therapeutic efficacy against a spectrum of childhood rhabdomyosarcomas (RMS) maintained as xenografts in immune-deprived mice. These xenografts were established from previously untreated tumors, and sublines were selected in mice for resistance to l-phenylalanine mustard (L-PAM). PTT.119 caused regression of four of six RMS lines established from untreated tumors, and demonstrated activity similar to that of L-PAM in this model. Against tumors Rh18/L-PAM and Rh28/L-PAM, selected in situ for L-PAM resistance, PTT.119 had no significant activity. Rh28/L-PAM was cross-resistant also to oxazophosphorine mustards (ifosfamide, cyclophosphamide), and both tumors were cross-resistant to adriamycin and vincristine. PTT.119 caused hematologic toxicity similar to thet of L-PAM, characterized by a marked decrease in white blood cells and thrombocytopenia.Abbreviations PTT.119 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)-aminophenyl]-L-alanyl-L-methionine ethyl ester HCl - L-PAM L-phenylalanine mustard - VCR vincristine - ADR adriamycin - CTX cyclophosphamide - Ifos ifosfamideSupported by PHS grant CA23099 from the National Cancer Institute and by American Lebanese Syrian Associated Charities Offprint requests to: Peter J. Houghton, Laboratories for Developmental Therapeutics, Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Box 381, Memphis, TN 38101, USA