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In Vivo and in Vitro Enhanced Antitumor Effects by Pentoxifylline in Human Cancer Cells Treated with Thiotepa¹

Departments of Surgery [H. J. F., A. T. P., Z. C.] and Pathology [P. B. G.], Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114; National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [M. C. A.]; and Dana Farber Cancer Institute, Boston, Massachusetts 02115 [A. B. P.]

Methylxanthines enhance lethality of alkylating agents in human cancer cells, a phenomenon attributed to the prevention of DNA repair. Pentoxifylline is a nontoxic methylxanthine, used clinically for claudication. Using human cancer cells in culture or in a mouse xenograft model, we studied combination treatments with alkylating agents and pentoxifylline or other methylxanthines.

With human bladder cancer cells in culture, cytotoxicity of thiotepa was increased up to 10-fold (P < 0.01) by posttreatment with pentoxifylline, with a major clinical metabolite of pentoxifylline, or with caffeine; the pentoxifylline concentrations required (0.4–1.0 mM) are clinically achievable in the bladder after nontoxic p.o. doses.

With human bladder or breast cancer xenografts in a modified subrenal capsule assay, enhancement of thiotepa was also observed by in vivo posttreatment with pentoxifylline. In contrast, these combinations produced no increased toxicity to normal tissues in these animals, measured by weight, lethality, or histological changes of the normal bladder urothelium.

These results provide evidence for a novel approach to improve the therapeutic index of thiotepa and other alkylators, used for topical therapy of bladder cancer and, possibly, systemic therapy of other malignancies.

¹ Supported by NIH Grants CA01157 and CA22427.

² To whom requests for reprints should be addressed, at Massachusetts General Hospital Cancer Center, Cox 6, Fruit St., Boston, MA 02114.

Received 9/14/87. Revised 3/ 1/88. Accepted 4/25/88.

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