Cellular pharmacology of gemcitabine

A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.

A phase I clinical, plasma, and cellular pharmacology study of gemcitabine.

The evolution of iron chelators from a range of primordial siderophores and aromatic heterocyclic ligands has lead to the formation of a new generation of potent and efficient iron chelators. For example, various siderophore analogs and synthetic ligands, including ICL670A [4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid], 4'-hydroxydesazadesferrithiocin, and Triapine, have been developed from predecessors and illustrate potent iron-mobilizing or antineoplastic activities. This review focuses on the evolution of iron chelators from initial lead compounds through to the development of novel chelating agents, many of which show great potential to be clinically applied in the treatment of iron overload disease and cancer.

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

PURPOSE: Few chemotherapy agents are active in leiomyosarcoma (LMS), particularly LMS that has progressed after doxorubicin treatment. We sought to determine the response to gemcitabine plus docetaxel among patients with LMS. PATIENTS AND METHODS: Patients with unresectable LMS of uterine (n = 29) or other (n = 5) primary sites who did not respond to zero to two prior chemotherapy regimens were enrolled onto a phase II study of gemcitabine 900 mg/m2 intravenously (IV) on days 1 and 8 plus docetaxel 100 mg/m2 IV on day 8 with granulocyte colony-stimulating factor given subcutaneously on days 9 to 15, delivered every 21 days. Patients with prior pelvic radiation received 25% lower doses of both agents. Gemcitabine was delivered over 30 or 90 minutes in cycles 1 and 2 and by 90-minute infusion in all subsequent cycles. Pharmacokinetic studies assessed in vivo differences in gemcitabine concentrations with different rates of infusion. RESULTS: Thirty-four patients (median age, 55 years; range, 32 to 74 years)...

Gemcitabine and Docetaxel in Patients With Unresectable Leiomyosarcoma: Results of a Phase II Trial

Purpose: To conduct a randomized phase II trial of dose-intense gemcitabine using a standard 30-minute infusion or the fixed dose rate (FDR) infusion (10 mg/m2/min) in patients with pancreatic adenocarcinoma. Patients and Methods: In this prospective trial, patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2 gemcitabine over 30 minutes (standard arm) or 1,500 mg/m2 gemcitabine over 150 minutes (FDR arm) on days 1, 8, and 15 of every 4-week cycle. The primary end point of this trial was time to treatment failure. Secondary end points included time to progression, median survival, safety, and pharmacokinetic studies of gemcitabine. Results: Ninety-two patients were enrolled onto this study; 91% of the patients had metastatic disease. Time to treatment failure was comparable in both treatment groups; however, the median survival for all patients was 5.0 months in the standard arm and 8.0 months in the FDR arm (P = .013). For patients with metastases, the medi...

Randomized Phase II Comparison of Dose-Intense Gemcitabine: Thirty-Minute Infusion and Fixed Dose Rate Infusion in Patients With Pancreatic Adenocarcinoma

The new deoxycytidine analogue 2',2'-difluorodeoxycytidine (dFdC) is a specific inhibitor of DNA synthesis that has marked cytotoxicity and therapeutic activity. A 2-hr incubation with 0.1-10 microM dFdC decreased cellular viability 78-97%. This treatment reduced deoxynucleoside triphosphate pools, similar to the action of the ribonucleotide reductase inhibitor hydroxyurea. The most pronounced decrease occurred in the dCTP pool, quantitatively followed by the decrease of dATP, dGTP, and dTTP. In contrast, inhibition of DNA synthesis by arabinosylcytosine did not affect the dCTP level, whereas dATP, dGTP, and dTTP pools increased, but less than 2-fold. The incorporation of [5-3H]cytidine into the dCTP pool, a measure of ribonucleotide reductase activity in whole cells, was reduced to 3% of controls by 0.1 microM dFdC, but to only 40% by 0.1 microM ara-C. Each drug decreased incorporation of [5-3H]cytidine into DNA to a similar extent (greater than 94%), suggesting limitation by a reaction proximal to this step. The cellular concentration of dFdC 5'-diphosphate was 0.3 microM at 50% inhibition of the in situ activity of ribonucleotide reductase. Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase.

Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine.

The clinical efficacy of ara-C is limited by a rapid elimination of the active triphosphate by target cells. The nucleoside antimetabolite, 2',2'-difluorodeoxycytidine, accumulates in leukemia cells as the respective 5'-triphosphate dFdCTP. In contrast to ara-C triphosphate, dFdCTP is eliminated with biphasic kinetics that exhibit a terminal half-life that approaches the cell cycle time. The cellular pharmacokinetics of dFdCTP may explain the unusual dose schedule and spectrum of efficacy against murine tumors.

Pharmacokinetics of the 5'-triphosphates of arabinosylcytosine and 2',2'-difluorodeoxycytidine in L1210 cells.

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Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine.

Pharmacokinetics of the 5'-triphosphates of arabinosylcytosine and 2',2'-difluorodeoxycytidine in L1210 cells.