Development and activities of a new melphalan prodrug designed for tumor-selective activation

Bioconjugate Chemistry
D E KerrV M Vrudhula

Abstract

The synthesis of C-Mel, a cephalosporin carbamate derivative of the clinically used alkylating agent melphalan, is described. C-Mel was designed as an anticancer nitrogen mustard prodrug that releases melphalan upon tumor-specific activation by targeted beta-lactamase (bL). The Km and kcat values for bL hydrolysis of C-Mel were 218 microM and 980 s(-1), respectively. In vitro cytotoxicity assays with 3677 human melanoma cells demonstrated that C-Mel was 40-fold less toxic than melphalan and was activated in an immunologically specific manner by L49-sFv-bL, a recombinant fusion protein that binds to the melanotransferrin antigen on melanomas and on some carcinomas. L49-sFv-bL in combination with C-Mel led to regressions and cures of established subcutaneous 3677 tumors in nude mice. The effects were significantly greater than those of melphalan, which did not result in any long-term regressions in this tumor model. The therapeutic effects were comparable to those obtained in mice treated with the previously described L49-sFv-bL/7-(4-carboxybutanamido)-cephalosporin mustard (CCM) combination. However, C-Mel may be more attractive than CCM for clinical development since the released drug is clinically approved.

References

Feb 21, 1996·Journal of the National Cancer Institute·R G Melton, R F Sherwood

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Citations

Oct 8, 1999·Pharmacology & Therapeutics·G M Dubowchik, M A Walker
Dec 18, 2001·Advanced Drug Delivery Reviews·P D Senter, C J Springer
May 6, 2003·Bioorganic & Medicinal Chemistry Letters·Xiaoping TangPeng George Wang
Jun 15, 2007·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Sachin MittalGordon L Amidon
Jul 5, 2005·Expert Opinion on Investigational Drugs·K D BagshaweS K Sharma
Oct 16, 2016·Expert Opinion on Biological Therapy·Surinder K Sharma, Kenneth D Bagshawe
Mar 22, 2003·The Journal of Pharmacology and Experimental Therapeutics·Hidekazu ToyobukuAkira Tsuji
Mar 6, 2004·Pharmacological Reviews·Martijn RooseboomNico P E Vermeulen
Feb 5, 2003·Bioorganic & Medicinal Chemistry Letters·Vivekananda M VrudhulaPeter D Senter

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