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Characteristics of Bleomycin-resistant Phenotypes of Human Cell Sublines and Circumvention of Bleomycin Resistance by Liblomycin¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 [J. S. L., I. D. B., D. C. L., J. C. S., B. M.]; Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 [J. S. L.]; Department of Medical Oncology, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030 [R. A. N.]; and Department of Pharmacology, The George Washington University, Washington, DC 20037 [K. A. K.]

Three bleomycin (BLM)-resistant sublines were isolated from a human head and neck squamous cell carcinoma cell line (A-253); these sublines (C-10, D-10, and G-11) were 4-, 9-, and 21-fold resistant to BLM A₂, respectively. These sublines were selectively resistant to other members of the BLM class, namely BLM B₂, peplomycin, talisomycin S₁₀₆, and bleomycinic acid; none of the sublines displayed cross-resistance to vincristine, doxorubicin, cis-diamminedichloroplatinum or melphalan; only one subline (G-11) was cross-resistant to X-irradiation. None of the BLM-resistant cell lines demonstrated resistance to the novel BLM analogue liblomycin, which contains a lipophilic terminal amine. The cell cycle distributions of the clonally derived BLM-resistant cell populations were similar to the distribution of the clonally derived BLM-resistant cell populations were similar to the distribution of the parental cell population. In vitro BLM hydrolase activity in homogenates of D-10 and G-11 BLM-resistant cell lines was two- to threefold higher than that in homogenates of A-253 or C-10 cells. Nonetheless, no deamido BLM A₂ was found associated with any cell type or in the culture medium and more than 80% of the radioactivity in all cells appeared as unmetabolized BLM A₂ by high pressure liquid chromatography. Thus, the appearance of large quantities of the deamido BLM metabolite was not a prominent feature of acquired resistance to BLM in these human tumor cells.

The cellular accumulation of radiolabeled BLM A₂ by C-10 and G-11 cells during a 1-h incubation with [³H]BLM A₂ was that seen with A-253 and D-10 cells. C-10 cells maintained a lower nuclear content of radioactivity than A-253, G-11, or D-10 cells. Initial single strand DNA damage, based upon alkaline elution analysis, also was lower in C-10 cells compared to A-253 cells. D-10 cells, in contrast, exhibited high initial genomic DNA damage but demonstrated a greater repair rate than either A-253 or C-10 cells. Thus, multiple BLM-resistant phenotypes can be obtained from a population of human squamous carcinoma cells, and modification of the terminal amine in the BLM molecule can produce compounds capable of circumventing all of these BLM-resistant phenotypes. Liblomycin, which appears to be a nonclassical BLM, may be a useful therapeutic agent with a spectrum of activity distinct from other members of the BLM class.

¹ This work was supported by American Cancer Society Grants CH-316 and CH-274 and by USPHS Grants CA-01012, CA-43917, and CA-01135.

² To whom requests for reprints should be addressed, at Department of Pharmacology, 518 Scaife Hall, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261.

Received 2/23/88. Revised 6/28/88. Revised 9/16/88. Accepted 9/27/88.

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