Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytochrome P450 CYP1B1 is consistently overexpressed in tumour cells as compared to their normal counterparts, but its precise role in drug resistance is yet to be defined. It has been reported that transfection of CYP1B1 results in increased resistance to docetaxel in V79 cells (McFadyen et al, 2001). In this study, we analysed changes in expression of CYP1B1 mRNA associated with pulse selection of MCF-7 cells with docetaxel. Docetaxel-selected MCF-7 cells (MCF-7 Txt), which showed increased resistance to this drug as compared to parental MCF-7 cells, showed a noteworthy increase in CYP1B1 mRNA expression, paralleled by increased ethoxyresorufin-O-deethylase (EROD) activity levels. This effect was not observed in cisplatin- or adriamycin-selected MCF-7 cells, or in docetaxel-selected colon, lung or pancreatic carcinoma cells. Short-term treatment with docetaxel induced CYP1B1 mRNA expression in MDA 453 and BT-20 breast carcinoma cells, but not in MCF-7 cells. Transfection of MCF-7 Txt cells with CYP1B1 siRNA did not significantly affect docetaxel-induced toxicity, but it decreased cell survival in the absence of drug. Preincubation of docetaxel with recombinant CYP1B1 did not affect drug toxicity in A549 cells. These results suggest that CYP1B1 does not directly inactivate docetaxel, but rather might promote cell survival in MCF-7 Txt cells, providing an explanation for its association with drug resistance.
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PMID:CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance. 1821 50

Small cell carcinoma of the gallbladder is very rare, but shows high malignant potential with frequent metastasis. Chemotherapeutic regimens for the treatment of gallbladder small cell carcinoma have not yet been established. In this study, we examined in vivo chemosensitivity tests for the GB-04-JCK human gallbladder small cell carcinoma, which were previously established as a serial-transplantable xenograft in nude mice. We used four anticancer drugs: docetaxel, irinotecan, nedaplatine and gemcitabine. Docetaxel maximally suppressed xenograft tumor growth in mice (P<0.01), and showed complete tumor regression after chemotherapy day 35. Irinotecan and nedaplatine suppressed tumor growth without complete regression (P<0.01). Gemcitabine did not affect tumor growth significantly. This in vivo experimental study proposed chemotherapeutic regimens for human gallbladder small cell carcinoma.
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PMID:In vivo chemotherapeutic profile of human gallbladder small cell carcinoma. 1899 40

Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide "pepducin," P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer.
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PMID:Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. 1962 69

Patients with advanced gastric carcinoma have still had bad prognosis despite advances in the modern treatment era. Docetaxel, cisplatin, 5-fluorouracil (DCF) is effective, but highly toxic regimen for advanced cases. In this study, we modified the standard doses of DCF (mDCF) to evaluate the effectiveness and side effects. From July 2005 to July 2008, 37 advanced gastric cancer patients treated with at least one course of mDCF protocol as first-line treatment were included. The mDCF protocol included 60 mg/m(2) docetaxel and cisplatin for 1 day and 600 mg/m(2)/day, 5-flourouracil infusion for 5 days, repeated every 3 weeks. No patients used prophylactic granulocte -colony stimulating factor. Of the patients, 28 were male and nine were female; the median age was 53 (23-65) years. Of them, 83.8% received at least four courses of chemotherapy and 64.9% completed the preplanned six courses of treatment. Eleven (29.7%) of those patients who received mDCF in the first-line treatment used the FOLFIRI (5-FU, folinic acit, irinotekan) regimen for the second-line treatment. Response rates were evaluated according to RECIST criteria in 30 out of 37 patients. The median follow-up time was 7.1 months. The longest follow-up time was 19.9 months. Two patients (5.4%) had complete response, nine (21.6%) had partial response, and 14 (37.9%) had stabilized disease; overall, the disease was controlled in 25 patients (64.9%) whereas five patients (13.5%) had progression. Median time to progression was 6.7 months and overall survival was 10 months. The assessment of patients for grade 3-4 toxicity revealed that while 5.4% had anemia and 8.1% had neutropenia, 5.4% nausea and 5.4% diarrhea. Neutropenic fever developed in two patients, requiring hospitalization. G-CSF was used in three patients. Two patients with neutropenic fever and two with severe anemia (total number 4; 10.8%) received delayed chemotherapy. Dose reduction was required in four patients (10.8%), one due to neutropenia, one due to nephrotoxicity, and two due to nausea. No patient died due to chemotherapy toxicity. This retrospective study suggested that mDCF might have comparable efficacy with classical DFC, with better toxicity profile. However, its small size and retrospective nature should be considered when interpreting the results.
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PMID:The efficacy and safety of reduced-dose docetaxel, cisplatin, and 5-fluorouracil in the first-line treatment of advanced stage gastric adenocarcinoma. 1963 62

A balanced translocation involving 11q23 (MLL gene) could be observed in therapy related leukemia (TRL) patients generally treated with topoisomerase II inhibitors. Few reports have been published on TRL following docetaxel administration. Herein, we report a patient who developed acute myelomonocytic leukemia (AMMoL) with t (9; 11) (p22; q23) following chemotherapy mainly consisted of docetaxel for advanced prostatic carcinoma. A 69-year-old man was treated with a systemic chemotherapy containing docetaxel (total dose = 585 mg) for hormone-refractory metastatic poorly differentiated prostate carcinoma. Although, no disease progression of the prostatic carcinoma was observed, AMMoL with t (9; 11) (p22; q23) developed only ten months later from the administration of docetaxel. Docetaxel was considered to be the cause of TRL because of the presence of t (9; 11) (p22; q23) translocation and clinical course.
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PMID:[Therapy related leukemia with 11q23 abnormality induced by chemotherapy consisted of docetaxel for advanced prostatic carcinoma: case report]. 1966 46

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.
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PMID:Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells. 1985 12

A primary head and neck adenocarcinoma is a comparatively rare disease, and surgical resection has been the first choice for its treatment. In the present study, we performed chemotherapy with weekly administration of docetaxel in 3 cases with unresectable or recurrent adenocarcinoma of the head and neck on an outpatient basis, resulting in long-term maintenance of the patients' QOL. Each case had submandibular gland carcinoma, parotid gland carcinoma, or parathyroid gland carcinoma. Their observation period was 42, 76, or 87 months, respectively. Docetaxel was administered for 18, 19, or 28 courses, respectively. No adverse events of grade 3 or higher were observed. The present results might suggest that it is possible to treat patients with adenocarcinoma in the head and neck without decreasing patients' QOL.
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PMID:[Three cases of adenocarcinoma of the head and neck maintaining QOL by administration of docetaxel]. 2116 Feb 65

Docetaxel and interferon-beta (IFN-beta) were tested alone and in combination for their antiproliferative activity against the estradiol receptor (ER) positive MCF-7 and the ER negative MDA-MB231 breast cancer cell lines. Cell growth inhibition was determined after a 3 day incubation by the sulforhodamine B assay. The antiproliferative effects of the drug combinations were analysed using Berenbaum's hyperplane theorem to determine additive, synergistic and antagonistic effects. Docetaxel was found to be equally effective in inhibiting cell growth of both cell lines. On the other hand MCF-7 cells were more sensitive to the antiproliferative activity of IFN-beta than MDA-MB231 cells. At low docetaxel:IFN-beta molar concentration ratios a synergistic interaction was observed for MCF-7 cells, whereas an additive interaction was found for MDA-TMB231 cells. Higher molar ratios resulted in additive interactions on MCF-7 and antagonistic interactions on MDA-MB231 cells. MCF-7 cells seem to be more sensitive to treatment by the combination of docetaxel and IFN-beta than the MDA-MB231 cells. Therefore an ER positive breast carcinoma may possibly profit by the combination of docetaxel and IFN-beta, but further studies are necessary to clarify the therapeutic usefulness and optimal scheduling of the drug combination.
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PMID:Synergistic and antagonistic interactions between docetaxel and interferon-beta on growth of human breast cancer cells in vitro. 2154 61

Taxotere(R), a synthetic taxoid, has shown strong antitumor activity in vitro, in animal models and in human ovarian and breast carcinomas and malignant melanoma xenografts. Using clonogenic microassays with agar-containing glass capillaries we confirmed the potent inhibition of Taxotere(R) on the colony formation of murine bone marrow cells (GM-CFC: IC50 = 2.3 x 10(-8) M), human myeloid K562 (IC50 = 4.6 x 10(-9) M), HL-60 leukemia (IC50 = 4.6 x 10(-10) M) and KB human squamous carcinoma cells (IC50 = 2.1 x 10(-9) M). Thus, these tumor cells were 5 to 50 times more sensitive to Taxotere(R) than normal GM-CFU-C. In comparison, Taxotere(R) was found to be 50 to 350 fold more effective on the same tumor cells than cis-platin on the basis of the IC50 values. It is noteworthy that dose-response curves of Taxotere(R) and cis-platin presented different shapes suggesting that Taxotere(R) may have a more favorable therapeutic index. Moreover, Taxotere(R) was also able to induce HL-60 cells to differentiate to monocytes between 10(-10) and 10(-9) M and K562 cells between 10(-9) and 10(-8) M. The differentiation inducing capacity of Taxotere(R) was inversely related to the loss of proliferation potential and occurred at concentrations that did not significantly affect cell viability; hence a direct cytotoxic killing effect may be precluded. Thus, the antiproliferative activity of Taxotere(R) may be attributed not only to its spindle poison like action, but also to its differentiation inducing capacity. These data suggest the need for further studies to evaluate Taxotere(R) in' combination cytotoxic-differentiation therapy.
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PMID:Taxotere(R) inhibits the proliferation and induces the differentiation of hl-60 and k562 human myeloid-leukemia cells in-vitro. 2157 42

Epstein-Barr virus (EBV) is associated with human cancers such as nasopharyngeal carcinoma, Burkitt's lymphoma, Hodgkin's disease, and gastric carcinoma (GC). EBV is associated with about 10% of all GC cases globally. EBV-associated GC has distinct features from EBV-negative GC. However, it is still unclear if EBV infection has any effect on GC chemoresistance. Cell proliferation assay, cell cycle analysis, and active caspase Western blot revealed that the EBV-positive GC cell line (AGS-EBV) showed chemoresistance to docetaxel compared to the EBV-negative GC cell line (AGS). Docetaxel treatment increased expression of Bax similarly in AGS and AGS-EBV cell lines. However, Bcl-2 induction was markedly higher in AGS-EBV cells, after docetaxel treatment. Although docetaxel increased the expression of p53 to a similar extent in both cell lines, induction of p21 in AGS-EBV cells was lower than in AGS cells. Furthermore, expression of survivin was higher in AGS-EBV cells than in AGS cells following docetaxel treatment as well as at basal state. EBVlytic gene expression was induced by docetaxel treatment in AGS-EBV cells. The results suggest that EBV infection and lytic induction confers chemoresistance to GC, possibly by regulating cellular and EBV latent and lytic gene expression.
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PMID:Association between Epstein-Barr virus infection and chemoresistance to docetaxel in gastric carcinoma. 2162


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