2',2'-Difluorodeoxycytidine (
LY 188011,
Gemcitabine) is a novel
pyrimidine antimetabolite with promising activity in preclinical models for
leukemia and solid
tumors. Phase I clinical trials with the agent are ongoing. In order to better define types of
tumors with clinical sensitivity to
Gemcitabine (to help target phase II trials), we have studied the antitumor effects of this agent against a variety of freshly explanted human
tumor specimens using an in vitro capillary soft
agar cloning system. Final concentrations of 2.0-200 micrograms/ml were used for short-term (1 h) and continuous incubations experiments. Using a short-term incubation, 94/215 (44%)
tumor specimens were evaluable for the determination of antitumor activity. The most common
tumor types studied included colorectal, breast, non-small cell lung,
ovarian cancer, kidney and
melanoma. A concentration-dependent increase in the frequency of inhibited
tumor specimens was noted (2 micrograms/ml: 6/94 specimens, 20 micrograms/ml: 13/94 specimens, 200 micrograms/ml:33/94 specimens; p less than 0.0001). A similar increase in
tumor growth inhibition was found using a continuous incubation (2 micrograms/ml: 0/14 specimens, 20 micrograms/ml: 1/14 specimens, 200 micrograms/
ml: 7/14 specimens; p less than 0.001). We conclude that
Gemcitabine is an active
antitumor agent against
tumor colony forming units from a variety of human
malignancies if sufficiently high concentrations can be achieved. The agent should be evaluated for Phase II clinical activity against those
tumor types.