REGRESSIONS AND CURES OF MELANOMA XENOGRAFTS FOLLOWING TREATMENT WITHMONOCLONAL-ANTIBODY BETA-LACTAMASE CONJUGATES IN COMBINATION WITH ANTICANCER PRODRUGS

Cephalosporin doxorubicin (C-Dos) and 7-(4-carboxybutanamido)-cephalos porin mustard (CCM) are prodrugs that are catalytically converted by E nterobacter cloacae beta-lactamase (bL) to the active anticancer agent s doxorubicin and phenylenediamine mustard, respectively. Both prodrug s were less cytotoxic to the 3677 human melanoma line than their respe ctive drugs and were activated in an immunologically specific manner b y 96.5-bL, a mAb-bL conjugate that binds to 3677 cell surface antigens . Similar results were obtained using the CCM prodrug on SK-MEL 28 hum an melanoma cells. Experiments in mice with established s.c. 3677 tumo rs demonstrated that although no tumors were cured in mice receiving t he 96.5-bL/C-Dol combination, the activities mere greater than those o btained from systemic doxorubicin treatment or from administration of the nonbinding conjugate P1.17-bL in combination with C-Dox. In contra st, when CCM was used as a prodrug, cures of established 3677 tumors w ere obtained in 80% of the 96.5-bL treated animals. This combination w as also able to induce regressions of large 3677 tumor masses (800 mm( 3)) without any apparent toxic side effects. We conclude that 96.5-bL in combination with C-Dox or CCM has greater antitumor activity than s ystemic treatment with the corresponding drugs and that CCM is a more effective prodrug than C-Dox for treating human 3677 melanoma xenograf ts.