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 Google Scholar Google Scholar Articles by Ganapathi, R. Articles by Iliakis, G. Search for Related Content PubMed PubMed Citation Articles by Ganapathi, R. Articles by Iliakis, G.

Modulation of Adriamycin and N-Trifluoroacetyladriamycin-14-valerate Induced Effects on Cell Cycle Traverse and Cytotoxicity in P388 Mouse Leukemia Cells by Caffeine and the Calmodulin Inhibitor Trifluoperazine¹

Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44106 [R. G., D. G., H. S.]; University of Iowa, Iowa City, Iowa 52242 [A. Y.]; and Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [G. I.]

1,3,7-Trimethylxanthine "caffeine" (CAF) is reported to induce a differential effect on the cytotoxicity of the DNA intercalators actinomycin-D versus Adriamycin (ADR). In the present study the effect of caffeine and/or trifluoperazine in modulating cell cycle traverse, drug accumulation, and cytotoxicity of anthracyclines was evaluated. The survival in soft agar of P388 mouse leukemia cells treated with ADR (0.05–0.25 µg/ml) alone for 1 h was 1.2- to 3-fold lower when the cells were incubated for 24 h in drug-free medium versus medium supplemented with 2 mM CAF. In contrast, for P388 cells treated with ADR in the presence of 2 mM CAF for 1 h and subsequently incubated for 24 h in the absence or presence of 2 mM CAF, cell kill based on colony formation in soft agar was 2- to 20-fold lower than in ADR-treated cells never exposed to 2 mM CAF. In cells treated continuously for 24 h with ADR (0.01–0.05 µg/ml) or the DNA nonbinding ADR analogue N-trifluoroacetyladriamycin-14-valerate (AD32) (0.05 and 0.1 µg/ml) the survival in soft agar was 3- to 20-fold higher in the presence versus the absence of 2 mM CAF. The decreased cytotoxicity in cells treated with ADR or AD32 in the presence of CAF was accompanied by a significant reduction in the accumulation of cells in G₂. However, in cells treated with ADR or AD32 in the presence of 2 mM CAF plus 5 µM trifluoperazine the decreased G₂ accumulation was not accompanied by a reduction in anthracycline cytotoxicity. The modulation by CAF of ADR and AD32 cytotoxicity did not correlate with decreased cellular ADR and AD32 accumulation. Results from this study indicate that CAF markedly reduces the cytotoxicity of ADR or AD32 and trifluoperazine circumvents the effects of CAF.

¹ Supported by USPHS Grant 1R01 CA 35531 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at the Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.

Received 2/12/86. Revised 7/ 1/86. Accepted 7/31/86.