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 Munger, C. Articles by Gewirtz, D. Search for Related Content PubMed PubMed Citation Articles by Munger, C. Articles by Gewirtz, D.

Evidence for Inhibition of Growth Related to Compromised DNA Synthesis in the Interaction of Daunorubicin with H-35 Rat Hepatoma¹

Departments of Pharmacology/Toxicology and Medicine, Medical College of Virginia, Richmond, Virginia 23298-0230

The H-35 rat hepatoma is relatively insensitive to the anthracycline antibiotic, daunorubicin (DNR), requiring 0.25 µM daunorubicin for inhibition of cell proliferation by 50%. Studies were undertaken to investigate the basis for the apparent intrinsic resistance in this cell line. The relative insensitivity of the H-35 cells to DNR is not a function of metabolic inactivation of DNR to deoxyaglycone derivatives; after a 2-h incubation, less than 10% of drug is metabolized, exclusively by conversion to daunorubicinol. The limited toxicity of DNR to the rat hepatoma may be explained, in part, by the absence of DNA strand breaks at daunorubicin concentrations up to 1 µM while higher (supraclinical) DNR concentrations (5 and 10 µM) produce direct, "non-protein-associated" DNA strand breaks. Limited daunorubicin toxicity in this tumor cell line may also be related to the apparent absence of free radical-mediated cellular damage as the free radical scavengers dimethyl sulfoxide, catalase, methanol, and mannitol fail to reverse the inhibitory effect of 1 µM DNR on cell proliferation. Daunorubicin does not induce leakage of the cytoplasmic enzyme, glutamic oxaloacetate transaminase, or diminish mitochondrial enzyme function. Conversely, while drug effects on RNA synthesis are small, and protein synthesis is minimally diminished, inhibition of cell proliferation corresponds closely with inhibition of DNA synthesis.

¹ Supported by Public Health Service Grant CA37762 from the National Cancer Institute. Presented, in part, at the 78th Annual Meeting of the American Association for Cancer Research (Proc. Am. Assoc. Cancer Res., 28: 268, 1987).

² To whom correspondence should be addressed.

Received 9/ 8/87. Revised 1/19/88. Accepted 1/29/88.

This article has been cited by other articles:

				L. P. Swift, A. Rephaeli, A. Nudelman, D. R. Phillips, and S. M. Cutts Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II-Mediated Form of Cell Death. Cancer Res., May 1, 2006; 66(9): 4863 - 4871. [Abstract] [Full Text] [PDF]