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¹ Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, Uppsala, Sweden; ² Department of Chemistry, Medicinal Chemistry, Göteborg University, Göteborg, Sweden; ³ Karolinska Pharmacy and ⁴ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; ⁵ Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden

Requests for Reprints: Joachim Gullbo, Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, SE-751 85, Uppsala, Sweden. Phone: 46-18-6115250; Fax: 46-18-518237. E-mail: Joachim.Gullbo{at}medsci.uu.se

Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester) has been suggested as the main contributor to PTC activity. In contrast to its analogue melphalan, m-L-sarcolysin never reached clinical use. To allow a direct comparison, the corresponding melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester) was synthesized and its activity was compared with that of P2; the activities of melphalan and m-L-sarcolysin were studied in parallel. Cytotoxic activity in human tumor cell lines and some fresh human tumor specimens were analyzed as well as effects on cellular metabolism, macromolecular synthesis, and preliminary evaluation of the cell death characteristics. The results show that melphalan and m-L-sarcolysin display similar activity in these systems and that the tripeptides were more active than their parent monomers. Surprisingly however, the melphalan containing tripeptide J3 demonstrated a significantly more rapid and stronger activity than the m-L-sarcolysin analogue P2. Finally, the in vivo toxicity and activity of melphalan and J3 were investigated in mice bearing human leukemia cells in s.c. fibers. The in vitro results seem translatable into the in vivo situation, demonstrating better antileukemic effect of J3 but similar side effects as melphalan.

¹ Unpublished data.

Received 7/21/03; revised 9/15/03; accepted 9/16/03.