This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Svensson, H. P. Articles by Wallace, P. M. Search for Related Content PubMed PubMed Citation Articles by Svensson, H. P. Articles by Wallace, P. M.

In Vitro and In Vivo Activities of a Doxorubicin Prodrug in Combination with Monoclonal Antibody ß-Lactamase Conjugates

Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121

A cephalosporin derivative of doxorubicin (C-Dox) was evaluated as a prodrug for activation by mAb conjugates of the ß-lactamase from Enterobacter cloacae P99 (ßL; EC 3.5.2.6). The conjugates consisted of ßL and the F(ab') fragments of either of the mAbs L6, P1.17, or 96.5. L6 binds to antigens on a variety of carcinomas, including the two lung adenocarcinoma cell lines H2981 and H2987 used in this study. 96.5 binds to the melanoma-associated antigen p97, and P1.17 was used for the control conjugate. C-Dox was found to be less cytotoxic to three different tumor cell lines in vitro compared to the parent drug doxorubicin (Dox). Immunospecific activation took place when the cells were pretreated with ßL conjugates that could bind to antigens on the tumor cells. In vivo toxicity and pharmacokinetics studies in athymic female nu/nu mice revealed that C-Dox was at least 7-fold less toxic than Dox (on a molar basis), despite the fact that a 320-fold greater area-under-the-curve (blood concentration versus time) of C-Dox compared to Dox was obtained 0–2 h after administration of the two agents. Pharmacokinetic studies at maximum tolerated doses in mice bearing xenografts of either H2981 or H2987 revealed that the intratumoral levels of Dox after treatment with L6-ßL in combination with C-Dox were higher than were obtained by either systemic treatment with Dox or a combination of P1.17-ßL and C-Dox. This finding suggested that the conversion of C-Dox to Dox was tumor specific and dependent on the presence of the targeted antigen. Furthermore, the best antitumor activity against both H2981 and H2987 tumors was obtained by treatment with L6-ßL and C-Dox compared to P1.17-ßL and C-Dox or Dox alone. Thus, higher levels of Dox corresponded to greater therapeutic effects in both of the tumor models studied.

¹ To whom requests for reprints should be addressed, at Bristol-Myers Squibb Pharmaceutical Research Institute, 3005 First Avenue, Seattle, WA 98121.

Received 12/ 1/94. Accepted 3/31/95.

This article has been cited by other articles:

				M. Rooseboom, J. N. M. Commandeur, and N. P. E. Vermeulen Enzyme-Catalyzed Activation of Anticancer Prodrugs Pharmacol. Rev., March 1, 2004; 56(1): 53 - 102. [Abstract] [Full Text] [PDF]

				Y.-R. Kao, J.-Y. Shih, W.-C. Wen, Y.-P. Ko, B.-M. Chen, Y.-L. Chan, Y.-W. Chu, P.-C. Yang, C.-W. Wu, and S. R. Roffler Tumor-associated Antigen L6 and the Invasion of Human Lung Cancer Cells Clin. Cancer Res., July 1, 2003; 9(7): 2807 - 2816. [Abstract] [Full Text] [PDF]

				G. K. Smith, S. Banks, T. A. Blumenkopf, M. Cory, J. Humphreys, R. M. Laethem, J. Miller, C. P. Moxham, R. Mullin, P. H. Ray, et al. Toward Antibody-directed Enzyme Prodrug Therapy with the T268G Mutant of Human Carboxypeptidase A1 and Novel in Vivo Stable Prodrugs of Methotrexate J. Biol. Chem., June 20, 1997; 272(25): 15804 - 15816. [Abstract] [Full Text] [PDF]