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Cytotoxic, Cell Cycle, and Chromosomal Effects of Methylxanthines in Human Tumor Cells Treated with Alkylating Agents¹

Surgical Oncology Unit, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114 [H. J. F.], and Department of Pharmacology, Harvard Medical School and Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [H. J. F., J. D. C., A. B. P.]

Human tumor cells, like rodent cells, are sensitive to effects of methylxanthines (MEX) on lethality, cell cycle delays, and chromosome aberrations after DNA damage by anticancer drugs. Enhanced cytotoxicity of alkylating agents was observed when T24 human bladder tumor cells in culture were exposed to nontoxic concentrations of MEX such as caffeine or pentoxifylline. Tumor cell lethality was increased up to 10-fold by either caffeine or pentoxifylline (1 mM) present during the first cell cycle (16–24 h) after exposure to nitrogen mustard (HN2) or thiotepa. Cycloheximide, a protein synthesis inhibitor, abolished the enhanced lethality produced by MEX. In these synchronized human tumor cells further kinetic studies revealed that HN2 (0.5 µM x 1 h) delayed transit through S phase by about 1–2 h, and this delay was prevented by MEX. After completion of S phase, HN2-treated cells were delayed 3–6 h in G₂, and MEX also prevented this delay, leading to mitoses at the rate of controls. Chromosome analysis of these mitotic cells revealed dramatic increases in aberrations induced by alkylator + MEX combinations. The greatest number of aberrations was seen in HN2-treated cells exposed briefly to MEX in late S-G2. In contrast, no increased chromosome damage was seen in cells exposed to MEX in mid-S phase. Taken together, our results are consistent with the model that MEX enhance lethality of alkylator-treated human tumor cells by preventing delays in cell cycle transit through G₂, leading to chromosome aberrations which are lethal. G₂ delays in human tumor cells may provide time for repair processes that are critical for survival after sublethal DNA damage by HN2 or other anticancer alkylating agents.

¹ Supported by USPHS Grant CA 01157 to H. J. F., Grant CA 22427 to A. B. P., and a grant from the Donaldson Charitable Trust.

² To whom requests for reprints should be addressed, at MGH Cancer Center, Fruit St., Boston, MA 02114.

Received 9/ 9/85. Revised 1/28/86. Accepted 1/30/86.

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