Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gemcitabine, or 2',2'-difluorodeoxycytidine (dFdC) is a new anticancer agent with significant activity against a broad spectrum of tumors either as a single agent or in combination with other active anticancer drugs. Studies in vitro and in vivo have demonstrated that dFdC produces cytotoxic synergism with cisplatin, or cis-diamminedi-choloroplatinum(II) (CDDP); however, the mechanism by which the synergism occurs has not been elucidated. We proposed that the nucleotide excision repair (NER) process, which is responsible for the cellular removal of CDDP-DNA adducts, may be a target for the mechanism of the cytotoxic synergism of dFdC and CDDP. Because the mismatch repair (MMR) pathway is involved in mediating CDDP cytotoxicity, making determination of the role of the NER in the cytotoxic synergism more complicated, and because tumors are often defective in MMR, we selected an NER-proficient, MMR-deficient, CP2.0 human colon carcinoma cell line as a model for this study. By an in vitro repair synthesis assay, we found that dFdC triphosphate (dFdCTP), the active metabolite of dFdC, inhibited the incorporation of [alpha-32P]dATP as well as the incorporation of [alpha-32P]dCTP, suggesting that the repair inhibition by dFdCTP does not result simply from competition for the incorporation site but rather is also due to prevention of chain elongation during the DNA resynthesis process. To determine whether the repair inhibition contributes to the cytotoxic synergism, we examined the effect of the constitutive expression of ERCC1 antisense RNA on the interaction of dFdC and CDDP. CP2.0 cells were transfected with pERCC1/AS, an ERCC1 antisense expression vector; eight hygromycine-resistant clones expressing various levels of the antisense RNA were selected for quantification of and correlation between the repair activity and cytotoxic synergism. The results show that stable expression of ERCC1 antisense RNA down-regulated the level of mRNA and repair activity; the down-regulation of the repair activity significantly correlated with the reduction of the cytotoxic synergism of the two agents. These data provide direct evidence to support the hypothesis that inhibition of the repair of CDDP-induced DNA lesions plays a critical role in dFdC-mediated cytotoxic synergism with CDDP in MMR-deficient tumor cells.
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PMID:Expression of ERCC1 antisense RNA abrogates gemicitabine-mediated cytotoxic synergism with cisplatin in human colon tumor cells defective in mismatch repair but proficient in nucleotide excision repair. 1074 96

There is a great need for new therapeutic agents for patients with advanced pancreatic cancer. The new dioxolane analogue troxacitabine was evaluated in two human pancreatic cancer xenograft models. The models used included the Panc-01 and MiaPaCa pancreatic cancer cell lines. Whereas there is certainly no absolute evidence that either of the in vivo models is predictive for clinical activity, there is at least some evidence that they may be helpful in selecting agents for clinical trials in patients with pancreatic cancer. Troxacitabine was administered i.v. to the animals at doses of 10 and 25 mg/kg on a daily x 5 regimen. Gemcitabine was used as a positive control. The end points for the study included tumor growth inhibition (TGI), final weight, and the number of partial and complete tumor responses in the animals. Troxacitabine was highly active against the Panc-01 model (n = 8), with TGI levels of 88.5% and 84.3% at the 10 and 25 mg/kg doses, respectively. The mean final tumor weights for animals given troxacitabine were also significantly smaller (P < 0.001) compared with vehicle controls. At the 10 mg/kg dose, there were three partial tumor shrinkages and one complete tumor shrinkage, whereas at the 25 mg/kg dose, there were three partial tumor shrinkages. Troxacitabine had less activity against the MiaPaCa model (n = 10) and, by traditional response criteria, would be considered inactive, with TGIs of 4% and 22.7% at the 10 and 25 mg/kg dose level, respectively. Of note is that in comparison with gemcitabine, troxacitabine was more efficacious against Panc-01 and was equally active against MiaPaCa. These in vivo results are encouraging and support the prospect of performing Phase II and perhaps Phase III trials with troxacitabine in patients with advanced pancreatic cancer.
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PMID:The new dioxolane, (-)-2'-deoxy-3'-oxacytidine (BCH-4556, troxacitabine), has activity against pancreatic human tumor xenografts. 1077 91

Both epidermal growth factor receptor (EGF-R) signaling mechanisms and angiogenesis have been evaluated as independent targets for therapy of human pancreatic carcinoma, but a link between the two processes has been identified only recently. This study evaluated whether EGF-R blockade therapy with anti-EGF-R antibody C225 inhibits pancreatic carcinoma growth and metastasis in an orthotopic nude mouse model via tumor-mediated angiogenesis and whether gemcitabine potentiates this effect. In vitro treatment of human pancreatic carcinoma L3.6pl cells with C225 inhibited EGF-R autophosphorylation, producing a maximum of 20% cytostasis. Treatment with C225 plus gemcitabine resulted in additive cytotoxic effects that increased with increasing gemcitabine concentrations. Dose-dependent decreases in expression of the angiogenic factors vascular endothelial growth factor and interleukin 8 (but not basic fibroblast growth factor) were observed in the C225-treated cells (mRNA and protein levels). In L3.6pl tumors established in the pancreas of nude mice, systemic therapy with C225 alone and C225 in combination with gemcitabine resulted in growth inhibition, tumor regression, and abrogation of metastasis; median tumor volume was reduced from 538 to 0.3 and to 0 mm3, respectively. Gemcitabine treatment alone reduced median tumor volume from 538 to 152 mm3. Liver metastases were present in 50% of the controls, 30% of the gemcitabine-treated animals, and 20% of C225-treated animals. No macroscopically visible liver metastases were observed in the combination treatment group. As early as 11 days after C225 treatment, the median percentage of proliferating cell nuclear antigen-positive cells was substantially reduced compared with gemcitabine treatment alone (26% versus 73%, respectively) versus controls (92%), correlating with in vivo blockade of EGF-R activation. Similarly after 11 days treatment, production of vascular endothelial growth factor and interleukin 8 was significantly lower in C225 and C225 plus gemcitabine-treated tumors versus gemcitabine-treated and control tumors. Significant differences in microvessel density were observed 18 days after C225 or combination treatments (but not gemcitabine alone) in direct correlation with the difference in percentage of apoptotic endothelial cells, as visualized by double immunofluorescence microscopy. These experiments indicate that therapeutic strategies targeting EGF-R have a significant antitumor effect on human L3.6pl pancreatic carcinoma growing in nude mice which is mediated in part by inhibition of tumor-induced angiogenesis, leading to tumor cell apoptosis and regression. Furthermore, this effect is potentiated in combination with gemcitabine.
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PMID:Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. 1081 19

New agents with high anti-tumor effects have been developed since 1990. Monotherapy with one of these agents, gemcitabine, was confirmed to be as effective as the standard chemotherapy regimen against NSCLC, and to have a lower toxicity profile. In addition, the combination of gemcitabine plus cisplatin can be expected to show a survival advantage. The combination therapy consisting of these two new anti-cancer agents is expected to show effectiveness equal to that of platinum-based combination chemotherapy. Gemcitabine is well tolerated, so that it can be a useful treatment for maintaining QOL among the elderly or in poor performance status patients with NSCLC. Considering that this agent is also effective against pancreatic cancer, further investigation for efficacy against other cancers is warranted.
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PMID:[Current status and future directions of gemcitabine in the treatment of non-small cell lung cancer and pancreatic cancer]. 1094 29

Gemcitabine (Gem) is a deoxycytidine analog that is effective against pancreatic cancer and other malignancies following conversion to the 5'-O-mono-, di- and tri-phosphate forms. We evaluated the cytotoxicity of GemMP[10], a novel multimeric form of 2'-deoxy-2',2"-difluorocytidine-5'-O-monophosphate (gemcitabine monophosphate) against three thyroid carcinoma cell lines established from anaplastic (8505C), papillary (B-CPAP) and poorly-differentiated papillary (BHT-101) cancer. GemMP[10] decreased tumor cell growth at concentrations ranging from 1 to 50 nM. These concentrations were 5- to 10-fold lower than those required for inhibition of tumor cell growth by monomeric Gem. GemMP[10] cytotoxicity occurred via induction of apoptosis. Flow cytometric analysis of GemMP[10] treated cells revealed growth arrest in S-phase. Fas-antigen expression was increased in thyroid cancer cells treated with GemMP[10], whereas Fas-L and Bcl-2 expression were not significantly affected. These results demonstrated that GemMP[10] is a potent cytotoxic agent that serves to induce apoptosis in association with increased Fas expression in cultured thyroid cancer cell lines.
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PMID:Antineoplastic activity of a novel multimeric gemcitabine-monophosphate prodrug against thyroid cancer cells in vitro. 1106 1

More than 50% of patients with pancreatic or biliary tract cancer are diagnosed in advanced and curatively unresectable tumor stages. To date, chemotherapeutic treatment yielded disappointing results in these patients with 5-year survival rates of 0-15%, leading to therapeutic nihilism in many patients. However, with the availability of new cytostatic agents as well as the introduction of the novel clinical endpoint "clinical benefit response" at least some improvements may be possible in patients with pancreatic cancer. Several randomized studies have shown a clinical and survival benefit for patients treated with chemotherapy as compared to patients treated with best supportive care alone. Gemcitabine was the first agent, which was investigated for its potential to improve symptoms as well as overall well being. A significant clinical benefit response can be achieved in up to 40% of patients with advanced pancreatic cancer. Gemcitabine is currently also investigated in combination chemotherapy regimens. First results with combination chemotherapy regimens such as cisplatin/gemcitabine have shown promising results. In addition, taxanes such as docetaxel also appear to have a certain activity in patients with pancreatic cancer. In contrast, topoisomerase I-inhibiting drugs seems to have no efficacy in the treatment of this disease. New and experimental therapeutic options such as angiogenesis-inhibition, matrixmetalloproteinase-inhibition or the use of monoclonal antibodies are currently evaluated within clinical studies. Only a few small studies reporting about chemotherapy in patients with biliary tract cancer have been published. This is mainly due to the rarity of this tumor entity, but also due to the rapid onset of symptoms such as hyperbilirubinemia, which will limit the number of potentially available drugs. 5-FU is the most widely investigated drug inducing remissions in 10-15% of patients. It is unclear whether new agents such as gemcitabine or the taxanes will led to an improvement of the prognosis of these patients. Although the recent advances in the treatment with these new therapeutic options are far from being satisfactory, it appears that a first small step ahead has been made the treatment of these diseases.
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PMID:[Current aspects of chemotherapy of metastatic pancreatic and biliary tract carcinomas]. 1106 8

Gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdCyd) has been shown to be a potent radiosensitizer in tumor cells both in vitro and in vivo. We evaluated the ability of dFdCyd to enhance the radiosensitivity of two human glioblastoma cell lines. The results demonstrated that U251 cells were more sensitive to the cytotoxicity of dFdCyd, and that dFdCyd was able to radiosensitize these cells. In contrast, D54 cells were more resistant to the cytotoxic effect of dFdCyd, and no radiosensitization occurred at any concentration of dFdCyd tested. Because radiosensitization by dFdCyd has been correlated with its ability to deplete dATP pools through inhibition of ribonucleotide reductase by dFdCyd diphosphate, we evaluated the metabolism of dFdCyd in both cell lines. At equitoxic concentrations of dFdCyd, both cell lines accumulated similar levels of the cytotoxic metabolite, dFdCyd triphosphate, as well as similar levels of dFdCyd monophosphate in DNA. In U251 cells, radiosensitizing concentrations of dFdCyd (10 or 25 nM; IC10 or IC50) depleted dATP by approximately 80% within 4 h. In contrast, 80 nM (IC50) was unable to deplete dATP by >30% within 4 h in D54 cells. Higher concentrations of dFdCyd or hydroxyurea, an inhibitor of ribonucleotide reductase that depleted dATP >90%, also did not produce radiosensitization in D54 cells. D54 cells were not resistant to radiosensitization because bromodeoxyuridine was able to induce radiosensitization. Because D54 cells express wild-type p53, whereas U251 cells express a mutant p53, the effect of dFdCyd and ionizing radiation on cell cycle progression was evaluated. Radiation alone produced a G1 block in D54 cells and a transient G2-M block in U251 cells. After a 24 h incubation with dFdCyd alone or in combination with ionizing radiation, U251 cells readily accumulated in S-phase, which remained elevated for at least 72 h, consistent with previous results in other mutant p53 cell lines. In addition, radiation enhanced the ability of dFdCyd to induce S-phase-specific cell death in U251 cells. In contrast, D54 cells showed a G1 block after dFdCyd and radiation exposure, with fewer cells in S-phase for at least 48 h after drug washout/irradiation. Furthermore, treatment with dFdCyd and/or radiation did not increase the amount of S-phase-specific cell death in D54 cells compared with control cells. These results suggest that the G1 block in D54 cells resulting from wild-type p53 induction prevented radiosensitization by dFdCyd.
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PMID:The role of cell cycle progression in radiosensitization by 2',2'-difluoro-2'-deoxycytidine. 1108 31

Unresectable pancreatic cancer has a dismal prognosis with a median survival of 3-5 months in untreated disease. Since the introduction of gemcitabine, pancreatic cancer may no longer be regarded a chemotherapy-resistant tumor. Treatment with single-agent gemcitabine achieved clinical benefit and symptoms improvement in 20-30% of patients. While 1-year survival was observed in 2% of 5-fluorouracil (5-FU)-treated patients, it was raised to 18% by single-agent gemcitabine. Good treatment tolerability and low incidence of side effects are clear advantages of single-agent gemcitabine. Improvement of efficacy is, however, expected from combination treatment. Gemcitabine and cisplatin given as first-line treatment in three studies achieved a median survival of 7.4-8.3 months. One-year survival was raised to 28% as reported in one study. Comparable activity was obtained by a combination of gemcitabine with 5-FU. Nine studies using gemcitabine in combination with standard-dose or high-dose 5-FU reported a median survival ranging from 5.5 to 13 months. Notwithstanding these promising results, recommendations regarding palliative chemotherapy of pancreatic cancer remain tentative and still need confirmation by presently ongoing phase III trials. Inclusion of pancreatic cancer patients into clinical trials should be a major goal. Outside clinical trials, patients should present with an adequate PS (Karnofsky-performance index greater than or = 70) to qualify for chemotherapy.
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PMID:Gemcitabine: progress in the treatment of pancreatic cancer. 1115 Sep 2

The ErbB receptor family is implicated in the malignant transformation of several tumor types and is overexpressed frequently in breast, ovarian, and other tumors. The mechanism by which CI-1033 and gemcitabine, either singly or in combination, kill tumor cells was examined in two breast lines, MDA-MB-453 and BT474; both overexpress the ErbB-2 receptor. CI-1033, a potent inhibitor of the ErbB family of receptor tyrosine kinases, reduced levels of activated Akt in MDA-MB-453 cells. This effect alone, however, did not induce apoptosis in these cells. Gemcitabine treatment resulted in a moderate increase in the percentage of apoptotic cells that was accompanied by activation of p38 and MAPK (ERK1/2). CI-1033 given 24 h after gemcitabine produced a significant increase in the apoptotic fraction over treatment with either drug alone. During the combined treatment p38 remained activated, whereas Akt and activated MAPK were suppressed. Substitution of CI-1033 with the phosphatidylinositol 3-kinase inhibitor LY294002 and the MAPK/ERK kinase inhibitor PD 098059 in combination with gemcitabine produced the same results as the combination of CI-1033 and gemcitabine. p38 suppression by SB203580 prevented the enhanced cell kill by CI-1033. In contrast to MDA-MB-453, BT474 cells exhibited activated p38 under unstressed conditions as well as activated Akt and MAPK. Treatment of BT474 cells with CI-1033 inhibited both the phosphorylation of Akt and MAPK and resulted in a 47% apoptotic fraction. Gemcitabine did not cause apoptosis in the BT474 cells. These data indicate that suppression of Akt and MAPK in the presence of activated p38 results in cell death and a possible mechanism for the enhanced apoptosis produced by the combination of CI-1033 and gemcitabine in MDA-MB-453 cells. Furthermore, tumors that depend on ErbB receptor signaling for survival and exhibit activated p38 in the basal state may be susceptible to apoptosis by CI-1033 as a single agent.
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PMID:Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. 1127 35

Gemcitabine has been shown to be an active agent in the treatment of pancreatic cancer. This study was conducted to prospectively examine the tolerance and early efficacy of adjuvant gemcitabine following radiotherapy with concurrent 5-fluorouracil (5-FU) for nonmetastatic pancreatic adenocarcinoma. Twenty-three patients, median age 64 years, were treated with combined modality therapy. Nine patients underwent tumor resection before chemoradiation; 14 patients with locally unresectable tumors received definitive chemoradiation. Radiotherapy utilized four fields to the tumor and lymphatics to 45 Gy, plus a lateral boost to 50.4 Gy. Concurrent 5-FU 500 mg/m(2)/day was administered on days 1-3 and 29-31, followed by 4 months of gemcitabine 1,000 mg/m(2)/week for 3 weeks (fourth week break). Adjuvant gemcitabine was well tolerated. Eighty-three percent of the patients completed three to four cycles. The primary dose-limiting toxicity was leukopenia, which was observed in 10 patients (43%). Nonhematologic toxicities were reported in five patients (22%). There were no cases of gemcitabine-induced radiation recall and there have been no deaths attributed to treatment toxicity. Median follow-up for the 23 patients was 12 months (range, 5-50); the actuarial median survival was 13 months. This report confirms that adjuvant gemcitabine following radiotherapy with concurrent 5-FU for nonmetastatic pancreatic adenocarcinoma can be safely administered.
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PMID:Gemcitabine following radiotherapy with concurrent 5-fluorouracil for nonmetastatic adenocarcinoma of the pancreas. 1129 Oct 97


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