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Selective Enhancement of Antitumor Activity of N-Acetyl Melphalan upon Conjugation to Monoclonal Antibodies

Research Centre for Cancer and Transplantation, Department of Pathology, The University of Melbourne, Parkville, Victoria 3052, Australia

Melphalan (MEL) is an aromatic alkylating agent which is useful for the treatment of a number of human cancers, including myeloma and ovarian cancer. However, like most cytotoxic drugs, MEL has side effects, due to its nonspecific effects on all or most cells. To overcome these nonspecific effects N-acetyl melphalan (N-AcMEL) was synthesized and found to be 75 times less toxic to tumor cells in vitro. However, when N-AcMEL was conjugated to monoclonal antibodies (MoAbs) to form N-AcMEL-MoAb conjugates the cytotoxic effect of MEL was restored, but with a difference in that the MEL could only act on cells which bound antibody. It was shown that, for N-AcMEL-MoAb conjugates, the N-AcMEL entered cells via the MoAb, by endocytosis, and not by the phenylalanine amino acid transport system. In addition, N-AcMEL-MoAb conjugates more effectively erradicated tumors in vivo than does free MEL or N-AcMEL. The N-AcMEL-MoAb conjugates therefore have high specific activity both in vitro and in vivo and a markedly reduced nonspecific toxicity, as N-AcMEL is relatively nontoxic to cells unless conveyed there by MoAb. In these respects the study offers a new approach to the use of chemotherapeutic agents in patients with cancer.

Received 2/11/86. Revised 8/26/86. Accepted 9/11/86.