Gene/Protein Disease Symptom Drug Enzyme Compound
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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gemcitabine (dFdC) and DMDC are new antimetabolites with good antitumor activities against various tumors which include human leukemic cell lines and a number of rodent and human solid tumors and human tumor. They are structurally related to cytarabine (Ara-C) which is known as one of the most effective drugs against adult acute leukemia, but many solid tumors are insensitive not been found to the drug. Gemcitabine acts as an inhibitor of ribonucleoside diphosphate reductase and inhibits DNA synthesis. Biochemically Gemcitabine is rapidly phosphorylated to dFdCTP which has a comparatively longer half-life than that of Ara-C, showing a therapeutic activity against tumors. In the phase I trials, the reported maximum-tolerated doses were 790 mg/m2 to 1370 mg/m2 at the schedule of 30 minutes i.v. infusion once a week for three weeks but higher dose levels (2,500 mg/m2 to 4,800 mg/m2) were reported in the schedule of prolongation of the infusion time. Reported toxicities were myelosuppression, fatigability, fever, appetite loss and skin rash. Toxicities were seemed to be mild. In USA, Europe and South Africa, phase II trials of Gemcitabine at the schedule of 30 minutes infusion once a week for three weeks followed by one week rest were performed against solid tumors (breast cancer, ovarian cancer, renal cancer, colorectal cancer, pancreas cancer, head and neck cancer, and lung cancer) and showed good responses to those tumors. DMDC was developed in Japan, and a phase I trial is currently on-going.
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PMID:[New antitumor antimetabolites--gemcitabine and DMDC]. 133 22

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.
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PMID:Activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human tumor colony forming units. 152 92

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.
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PMID:Preclinical in vivo activity of 2',2'-difluorodeoxycytidine (Gemcitabine) against human head and neck cancer. 198 86

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.
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PMID:Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). 236 94

Gemcitabine (2',2'-difluorodeoxycytidine, dFdC, LY188011) is a new deoxycytidine analog with preclinical antitumor activity in solid tumors from murine and human origin. Of particular importance is the fact that the therapeutic effects of gemcitabine at the maximum tolerated dose level are dependent on the administration schedule. This paper describes the sensitivity pattern of gemcitabine in human head and neck squamous cell carcinoma, ovarian carcinoma, and soft tissue sarcoma, all growing as xenografts in athymic nude mice. The drug was injected intraperitoneally in various schedules at equitoxic, maximum tolerated dose levels, resulting in a reversible weight loss that varied between 5% and 15%. Generally, it was found that treatment with 120 mg/kg gemcitabine, injected four times at 3-day intervals, was more effective than the schedules of daily (five times 2.5 to 3.5 mg/kg) or weekly (two times 240 mg/kg) injections. Other workers have shown that this 3-day interval schedule also was active in human pancreas and lung carcinoma xenografts. Additional experiments were performed on normal mice bearing the colon 26-10 murine colon carcinoma. The effect of a continuous intravenous infusion system was investigated by giving two injections of 15 mg/kg gemcitabine for 24 hours at a 7-day interval. Interestingly, the efficacy of treatment increased dramatically with this infusion schedule, producing complete remissions in most tumors. In conclusion, our data on the effect of gemcitabine in animal tumor models indicate that (1) the time interval between push injections is important when intermittent schedules are used and (2) continuous infusions over a 24-hour period can be very effective in in vivo models.
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PMID:Schedule-dependent antitumor effect of gemcitabine in in vivo model system. 748 44

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical activity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2-20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 x 10(3)/microliters (range 1.6-9.3) and the median absolute neutrophil (ANC) nadir was 2.0 x 10(3)/microliters (range 0.4-7.2). Thrombocytopenia - 100.0 x 10(3)/microliters was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0-245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemicitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.
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PMID:Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. 796 Jun 2

Gemcitabine is a new ara-C derivative and shows much more potent cytotoxic action than ara-C, which may be explained by the fact that its intracellular concentration can be maintained over a longer period. We investigated anti-tumor activity combining gemcitabine with cisplatin (CDDP) or vindesine (VDS) with a lung cancer line H-74 that was relatively insensitive to gemcitabine. Mice were observed for 8 weeks, including the 4 week treatment period and the subsequent 4 week drug-free period. The tumor growth inhibition rate, histological changes, and side effects were evaluated at 4 and 8 weeks after the initiation of therapy. The anti-tumor effects of treatment combining gemcitabine with CDDP or VDS were more potent and lasted longer than each drug separately. Statistical analysis shows that the treatment combining gemcitabine with CDDP was additive or synergistic at 4 and 8 weeks after initiation, whereas the treatment combining gemcitabine with VDS was only additive at 4 weeks after initiation and additive or synergistic at 8 weeks after initiation. The side effects of both combination groups were less than those observed in only CDDP or VDS-treated animals. These results suggest the usefulness of a combination therapy combining gemcitabine with CDDP or VDS in future clinical applications.
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PMID:[Antitumor activity of combination treatment combining gemcitabine with cisplatin or vindesine against human lung cancer xenografted in nude mice]. 797 19

One of the problems in the treatment of cancer is the development of resistance to anti-tumor agents when used repeatedly. We described the induction of resistance, cross-resistance to cisplatin (CDDP) or vindesine (VDS) and the side effects of gemcitabine, a new Ara-C derivative, in human lung cancers, Mqnu-1 or H-74 xenografted in nude mice. We investigated the effects of 4-week observation period. Gemcitabine was effective and did not show the acquired resistance when given repeatedly. In contrast, CDDP but not VDS, when given repeatedly, showed a decrease of the anti-tumor effect in the second course. Gemcitabine was still effective to the large tumor grown after CDDP or VDS therapy. Thus, gemcitabine may not develop resistance nor show cross-resistance to CDDP or VDS. In addition, repeated treatment with gemcitabine was much safer than CDDP or VDS. These results suggest that gemcitabine is a candidate for the first choice drug in cancer treatment.
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PMID:[Acquired resistance and cross-resistance of gemcitabine to cisplatin or vindesine in human lung cancer xenografted in nude mice]. 799 10

2',2'-Difluorodeoxycytidine (Gemcitabine, dFdCyd) is a cytotoxic agent which is active toward a variety of tumor cells. It has been shown that there are multiple intracellular sites of action which include ribonucleotide reductase and DNA polymerase. In these studies, the effects of dFdCyd on wild-type mouse leukemia L1210 cells and variant L1210 cell lines which had alterations at the ribonucleotide reductase site or at the deoxyribonucleoside kinase site were studied. For cell growth, the IC50 value for dFdCyd in wild-type L1210 cells was 3.1 nM. In the variant cell lines, the IC50 values were: hydroxyurea-resistant (HU), 3.3 nM; deoxyadenosine-resistant (Y8), 1.8 nM; pyrazoloimidazole/deoxyadenosine-resistant (ED2), 1.9 nM; and deoxyguanosine-resistant (dGuo-R), 44.7 nM. The dGuo-R cell line had a relatively specific loss of the deoxyribonucleoside kinase responsible for phosphorylating deoxyguanosine and cytosine arabinoside with little loss of the deoxycytidine kinase activity. DFdCyd had no effect on the total uptake of [14C]cytidine into the cells or incorporation into RNA. DFdCyd inhibited the conversion of [14C]cytidine to deoxycytidine nucleotides and incorporation into DNA. However, the incorporation of cytidine into DNA was inhibited to a greater extent than was the inhibition of in situ ribonucleotide reductase activity. Ribonucleotide reductase activity in cell-free extracts prepared from L1210 cells treated with dFdCyd (20 nM) overnight was reduced by 50%. These results show that cell lines which have increased levels of ribonucleotide reductase activity (HU and ED2) or loss of feedback inhibition by dATP (ED2 and Y8) are still sensitive to dFdCyd. The findings indicate that ribonucleotide reductase is not the primary site of inhibition by dFdCyd.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of 2',2'-difluorodeoxycytidine (Gemcitabine) on wild type and variant mouse leukemia L1210 cells. 836 54

Gemcitabine (2',2'difluoro-2'deoxycytidine, dFdC) is a synthetic antimetabolite of the cellular pyrimidine nucleotide metabolism. In a first series of in vitro experiments, the drug showed a strong effect on the proliferation and colony formation of the human androgen-sensitive tumor cell line LNCaP and the androgen-insensitive cell lines PC-3 and DU-145. Maximal inhibition occurred at a dFdC concentration as low as 30 nM. In contrast to the cell lines which were derived from metastatic lesions of prostate cancer patients, no inhibitory effects were found in normal primary prostatic epithelial cells at concentrations up to 100 nM. The effect of gemcitabine was reversed by co-administration of 10-100 microM of its natural analogue deoxycytidine. In view of a future clinical application of this anti-tumor drug in advanced prostatic carcinoma, we have compared the effect of gemcitabine on prostatic tumor cells with that on bone marrow granulopoietic-macrophage progenitor cells, because neutropenia is a common side effect of gemcitabine treatment. The time course of action on the two kinds of cells was markedly different. Colony formation of tumor cells was inhibited by two thirds at a gemcitabine concentration of about 3.5 nM. The same effect on granulopoietic-macrophagic progenitor cells required a concentration of 9 nM. Co-administration of deoxycytidine to gemcitabine-treated tumor cell cultures completely antagonized the effect of gemcitabine whereas addition of deoxycytidine after 48 hr of gemcitabine treatment could not prevent gemcitabine action on the tumor cells. In contrast, more than half of the granulopoietic-macrophagic progenitor cells could still be rescued by deoxycytidine administration after 48 hr. These findings and the marked difference in the susceptibility of neoplastic and normal prostatic cells suggest that gemcitabine is a promising substance which should be further evaluated as to its efficacy in the treatment of advanced prostatic carcinoma.
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PMID:Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells. 862 20


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