QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.005371v1 67/1/212    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Lu, H. Articles by Waxman, D. J. Search for Related Content PubMed PubMed Citation Articles by Lu, H. Articles by Waxman, D. J.

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts

Methoxymorpholinyl doxorubicin (MMDX) is a novel liver cytochrome P450 (P450)-activated anticancer prodrug whose toxicity toward cultured tumor cells can be potentiated up to 100-fold by incubation with liver microsomes and NADPH. In the present study, a panel of human liver microsomes activated MMDX with potentiation ratios directly correlated to the CYP3A-dependent testosterone 6-hydroxylase activity of each liver sample. Microsome-activated MMDX exhibited nanomolar IC₅₀ values in growth-inhibition assays of human tumor cell lines representing multiple tissues of origin: lung (A549 cells), brain (U251 cells), colon (LS180 cells), and breast (MCF-7 cells). Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4 activated MMDX more efficiently than rat CYP3A2 and that human P450s 3A5 and 3A7 displayed little or no activity. MMDX cytotoxicity was substantially increased in Chinese hamster ovary cells after stable expression of CYP3A4 in combination with P450 reductase. CYP3A activation of MMDX abolished the parent drug's residual cross-resistance in a doxorubicin-resistant MCF-7 cell line that overexpresses P-glycoprotein. CYP3A-activated MMDX displayed a comparatively high intrinsic stability, with a t_1/2 of 5.5 h at 37°C. MMDX was rapidly activated by CYP3A at low (1–5 nM) prodrug concentrations, with 100% tumor cell kill obtained after as short as a 2-h exposure to the activated metabolite. These findings demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-permeable cytotoxic metabolite and suggest that this anthracycline prodrug may be used in combination with CYP3A4 in a P450 prodrug activation-based gene therapy for cancer treatment.

Address correspondence to: Dr. David J. Waxman, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215. E-mail: djw{at}bu.edu

This article has been cited by other articles:

				C.-S. Chen, Y. Jounaidi, and D. J. Waxman ENANTIOSELECTIVE METABOLISM AND CYTOTOXICITY OF R-IFOSFAMIDE AND S-IFOSFAMIDE BY TUMOR CELL-EXPRESSED CYTOCHROMES P450 Drug Metab. Dispos., September 1, 2005; 33(9): 1261 - 1267. [Abstract] [Full Text] [PDF]

				D. S. Riddick, C. Lee, S. Ramji, E. C. Chinje, R. L. Cowen, K. J. Williams, A. V. Patterson, I. J. Stratford, C. S. Morrow, A. J. Townsend, et al. CANCER CHEMOTHERAPY AND DRUG METABOLISM Drug Metab. Dispos., August 1, 2005; 33(8): 1083 - 1096. [Abstract] [Full Text] [PDF]