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Selective Tumor Apoptosis by MF13, L-Prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline Ethyl Ester, a New Sarcolysin Containing Tripeptide¹

Division of Neoplastic Diseases, Department of Medicine, The Mount Sinai School of Medicine, New York, New York 10029

ID₅₀ and ID₉₀ values for L-prolyl-L-m-[bis(chloroethyl)amino]-phenylalanyl-L-norvaline ethyl ester HCl (MF13), were determined in four murine (leukemia, lymphoma, melanoma, and lung) and eight human cancer cell lines (two leukemia, prostate, kidney, colon, two melanoma, and breast). Cytotoxic activity was 2–5 times higher than that of sarcolysin {(L-3-[bis(2-chloroethyl)amino]-L-phenylalanine} against all leukemias and lymphomas, ID₅₀ 0.5–0.9 µM, and against human solid tumors, ID₅₀ 0.4–2.1 µM. Sensitivities of L-phenylalanine mustard-resistant and methotrexate-resistant L1210 cells were the same as the naive lines, ID₅₀ 0.5 µM. Apoptosis was confirmed by: (a) morphology, revealing chromatin condensation and nuclear fragmentation; (b) flow cytometry, showing changes in cell size and DNA integrity; and (c) DNA electrophoresis, demonstrating multiples of 180–200-bp DNA units. MF13 had no cytotoxicity against human peripheral blood lymphocytes at concentrations lethal to tumor cells (ID₅₀, 13.3 µM without and 11 µM with phytohemagglutinin stimulation) and failed to induce apoptosis. s.c. MF13 treatment of mice with advanced EL4 leukemic ascites yielded extensive apoptosis, with DNA degradation identical to that seen in vitro, and resulted in complete tumor regression in all treated mice. These results suggest MF13 as a potential chemotherapeutic agent.

¹ Supported by the T. J. Martell Memorial Foundation for Leukemia, Cancer, and AIDS Research.

² To whom requests for reprints should be addressed, at Mount Sinai School of Medicine, Box 1247, One Gustave Levy Place, New York, NY 10029. Phone: (212) 241-7382; Fax: (212) 860-7186; E-mail: jr2@academic.mssm.edu.

Received 5/ 5/97. Accepted 9/ 2/97.

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