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Effect of Novobiocin on the Antitumor Activity and Tumor Cell and Bone Marrow Survivals of Three Alkylating Agents¹

Department of Medicine, Beth Israel Hospital [J. P. E., L. E. S.], and Dana-Farber Cancer Institute [B. A. T., S. A. H., K. N. S. C., E. F.], Boston, Massachusetts 02115

Our previous in vitro studies demonstrated marked synergy with alkylating agents when novobiocin was present during and after alkylating agent exposure. To determine whether this effect is observed in vivo, novobiocin was administered daily for 3 days prior to alkylating agent treatment, during alkylating agent treatment, and for 2 days after completion of alkylating agent treatment. When combined with cis-diamminedichloroplatinum(II), 1,3-bis(2-chloroethyl)-1-nitrosourea, or cyclophosphamide, there was significant enhancement of the growth delay of the FSaIIC fibrosarcoma implanted s.c. in C3H mice when compared with alkylating agents alone. In a second assay using ex vivo studies of tumor cells exposed in vivo, single doses of 100 mg/kg of novobiocin followed by cis-diamminedichloroplatinum(II) resulted in a 3- to 4-fold increase in tumor cell killing by cis-diamminedichloroplatinum(II). At a dose of 100 mg/kg of 1,3-bis(2-chloroethyl)-1-nitrosourea there was about a 7-fold increase in tumor cell kill upon addition of novobiocin. Cyclophosphamide showed a dose response effect with novobiocin, reaching 13-fold at a dose of 300 mg/kg of cyclophosphamide. In all cases bone marrow elements were affected less than were neoplastic cells, suggesting that the combination of novobiocin and alkylating agents may be a clinically useful strategy.

¹ This work was supported by National Cancer Institute Grant 5PO1-CA38493 (B. A. T.).

² To whom requests for reprints should be addressed, at Department of Medicine, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02115.

Received 6/21/88. Revised 10/ 6/88. Accepted 10/25/88.