This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Ling, Y.-H. Articles by Perez-Soler, R. Search for Related Content PubMed PubMed Citation Articles by Ling, Y.-H. Articles by Perez-Soler, R.

In Vitro Cytotoxicity, Cellular Pharmacology, and DNA Lesions Induced by Annamycin, an Anthracycline Derivative with High Affinity for Lipid Membranes¹

Departments of Medical Oncology [Y. H. L., W. P., R. P] and Laboratory Medicine [L. Y. Y.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Division of Pharmaceutics, Ohio State University College of Pharmacy, Columbus, Ohio 43210 [T. G. B.]; and Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892 [Y. P.]

Annamycin (AN) is an anthracycline antibiotic with high affinity for lipid membranes which is being developed for clinical studies formulated in liposomes. We studied the in vitro cytotoxicity, cellular pharmacology, and DNA damage induced by AN in P388 cells sensitive and resistant to doxorubicin (DOX). AN was as cytotoxic as DOX against P388-sensitive cells and about 50 times more cytotoxic than DOX against P388-resistant cells (resistance index 5 for AN versus 250 for DOX). Cellular uptake of AN by sensitive cells was 2–3-fold higher than that of DOX. In resistant cells, cellular uptake of AN and DOX was approximately 65% and 30%, respectively, of the cellular uptake in sensitive cells. As a result, cellular uptake of AN by resistant cells was higher than uptake of DOX by sensitive cells. DOX was fully retained in sensitive cells while it was effluxed rapidly from resistant cells. In contrast, efflux of AN was similar in sensitive and resistant cells, thus suggesting that it is not mediated by P-glycoprotein. AN was more effective than DOX in inducing single DNA breaks, double DNA breaks, and DNA-protein cross-links, both in sensitive and resistant cells, although DNA damage was lower in resistant cells than in sensitive cells. DNA lesions induced by AN in resistant cells were similar to or greater than those induced by DOX in sensitive cells. These studies indicate that the lack of cross-resistance between DOX and AN appears to be related, at least in part, to the relatively higher cellular uptake of AN compared with DOX and is associated with the ability of AN to induce significant DNA damage in resistant cells.

¹ Supported in part by NIH Grant CA50270 and Argus Pharmaceuticals, Inc.

² To whom requests for reprints should be addressed, at Division of Medicine, Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Box 80, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 9/25/92. Accepted 1/27/93.

This article has been cited by other articles:

				A. V. Trevino, B. A. Woynarowska, T. S. Herman, W. Priebe, and J. M. Woynarowski Enhanced topoisomerase II targeting by annamycin and related 4-demethoxy anthracycline analogues Mol. Cancer Ther., November 1, 2004; 3(11): 1403 - 1410. [Abstract] [Full Text] [PDF]

				Y.-H. Ling, L. Liebes, J.-D. Jiang, J. F. Holland, P. J. Elliott, J. Adams, F. M. Muggia, and R. Perez-Soler Mechanisms of Proteasome Inhibitor PS-341-induced G2-M-Phase Arrest and Apoptosis in Human Non-Small Cell Lung Cancer Cell Lines Clin. Cancer Res., March 1, 2003; 9(3): 1145 - 1154. [Abstract] [Full Text] [PDF]