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Preclinical in Vivo Activity of 2',2'-Difluorodeoxycytidine (Gemcitabine) against Human Head and Neck Cancer¹

Departments of Otorhinolaryngology/Head and Neck Surgery [B. J. M. B., G. A. M. S. v. D., G. B. S.] and Medical Oncology [J. B. V.], Free University Hospital, Amsterdam, The Netherlands

2',2'-Difluorodeoxycytidine (dFdCyd, Gemcitabine) is a new deoxycytidine analogue with striking preclinical antitumor activity in solid tumors from murine and human origin. In this study, dFdCyd was tested for its antitumor effect in human tumor xenografts derived from squamous cell carcinoma of the head and neck (SCCHN). NMRI nude mice bearing s.c. growing tumors with a volume of 50 to 150 mm³ were given i.p. injections of a maximum tolerated dose of 120 mg/kg dFdCyd, every 3 days for four injections. A significant antitumor effect was observed in all five tested SCCHN tumor lines; in four of these lines the median tumor volume doubling time increased more than a 3-fold upon dFdCyd treatment. In two lines dFdCyd was curative (no tumor regrowth 90 days after treatment) in one of six and two of eight xenografts, respectively. Schedule dependency was investigated in three SCCHN lines, showing, in the two most sensitive lines, that treatment with a 3-day interval was superior to the schedules with daily or weekly injections. At equitoxic doses, dFdCyd was more active in this model than the drugs that are clinically used in SCCHN, i.e., cisplatin, methotrexate, 5-fluorouracil, and cyclophosphamide. dFdCyd is a good candidate for clinical trials with SCCHN patients.

¹ Supported by a grant of the "Nijbakker-Morra Stichting."

² To whom requests for reprints should be addressed, at the Department of Otorhinolaryngology/Head and Neck Surgery, Free University Hospital, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Received 5/ 1/90. Accepted 9/21/90.

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