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Increased Lethality of Calmodulin Antagonists and Bleomycin to Human Bone Marrow and Bleomycin-resistant Malignant Cells¹

Departments of Pharmacology [J. S. L., D-L. C.], Therapeutic Radiology [V. S. G.]., and Medicine [W. N. H.], Yale University School of Medicine, New Haven, Connecticut 06510

The effect of bleomycin and calmodulin antagonists on human cells was studied using a clonogenic assay. A 1-h exposure to nontoxic concentrations of the calmodulin antagonists melittin (0.5 µM), pimozide (5 µM), and chlorpromazine (20 µM) increased the lethality of bleomycin to human ovarian carcinoma cells (SK-OV). No increase was seen with chlorpromazine sulfoxide, which lacks calmodulin antagonistic activity. Maximum enhancement of bleomycin lethality by calmodulin antagonists was seen when the antagonist was present simultaneously with bleomycin rather than before or after bleomycin. The cytotoxicity of bleomycin to A-253 head and neck squamous carcinoma cells, which were 10-fold more sensitive to bleomycin alone compared to SK-OV cells, was not markedly altered by the presence of 20 µM chlorpromazine. Chlorpromazine, melittin, or pimozide also increased the toxicity of bleomycin to human granulocyte/macrophage and erythroid stem cell colonies. These results demonstrate that calmodulin antagonists can significantly increase the lethality of bleomycin to some but not all human tumor cells and that nonmalignant hematological human cells may also be affected by this combination.

¹ This work was supported by American Cancer Society Grants CH-316 and CH-302 and NIH Grants CA-25883, CA-01012, CA-08341, CA-06519, and CA-33652.

² To whom requests for reprints should be addressed, at Department of Pharmacology, P. O. Box 3333, 333 Cedar Street, Yale University, New Haven, CT 06510.

Received 6/27/85. Revised 12/11/85. Accepted 1/20/86.

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