COMBINATION OF THE NEW MINOR-GROOVE ALKYLATOR TALLIMUSTINE AND MELPHALAN

The benzoyl nitrogen mustard derivative of distamycin A, tallimustine, belongs to a new class of alkylating agents, known as DNA minor groov e alkylating agents. It alkylates adenine N3 with high sequence specif icity, causing no alkylation of guanine N7, the main site of alkylatio n of clinically used nitrogen mustards such as L-PAM. The present stud y investigated the in vivo antitumour activity of a combination of tal limustine and melphalan (L-PAM). Two murine tumours were used: i.p. (i ntraperitoneally) transplanted L1210 leukaemia and i.m. (intramuscular ly) transplanted M5076 ovarian reticulum cell sarcoma (M5). In L1210, which is only marginally sensitive to tallimustine, the combination of tallimustine 3 mg/kg i.p. with L-PAM 10 mg/kg i.p. was as effective a s 20 mg/kg L-PAM, which is the maximum tolerated dose. In M5, which is sensitive to both drugs, the combination was superior to either drug alone. The results suggest that the combination of tallimustine and L- PAM - or possibly in general, minor groove alkylators and major groove alkylators - may be therapeutically advantageous and therefore should be investigated clinically. (C) 1997 Published by Elsevier Science Lt d.