Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine)

• Published in: Cancer research (Chicago, Ill.) Vol. 50; no. 14; pp. 4417 - 4422
• Main Authors: HERTEL, L. W, BODER, G. B, KROIN, J. S, RINZEL, S. M, POORE, G. A, TODD, G. C, GRINDEY, G. B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-07-1990
• Subjects: Animals; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Chemotherapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Deoxycytidine - toxicity; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Female; Flow Cytometry; Humans; Leukemia L1210 - drug therapy; Leukemia P388 - drug therapy; Leukemia, Experimental - drug therapy; Male; Medical sciences; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Neoplasms, Experimental - drug therapy; Pharmacology. Drug treatments; Tumor Cells, Cultured - cytology; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Therapeutic efficiency; Human; Cell proliferation; Solid tumor; Toxicity; Leukemia; Rodentia; Malignant hemopathy; Deoxyribonucleoside; Malignant tumor; In vitro; In vivo; Vertebrata; Experimental disease; Mammalia; Antimetabolic; Deoxycytidine; Mouse; Animal; Fluorine Organic compounds; Inhibition; Pyrimidine nucleoside; Tumor cell
• ISSN: 0008-5472; 1538-7445

A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.