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

Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called carmethizole] is a new antitumor drug that has shown relatively broad activity in initial evaluations against several murine tumors and human tumor xenografts in vivo. The present studies were designed to address questions about carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1 mammary carcinoma, human NCI-H82 small-cell lung carcinoma, and human LOX amelanotic melanoma xenografts in athymic mice were used to determine the drug's activity against established disease; the NCI-H82 lung-tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. When injected i.p., carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The therapeutic effect of carmethizole was not route-dependent, as was evidenced by the similar delays observed in tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in tumor growth. Murine leukemias resistant to vincristine (VCR), amsacrine (AMSA), or methotrexate (MTX) were not cross-resistant to carmethizole. However, murine leukemias resistant to doxorubicin (ADR), melphalan (L-PAM), cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (ara-C), and 5-fluorouracil (5-FU) were cross-resistant to carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.
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PMID:Antitumor activity and cross-resistance of carmethizole hydrochloride in preclinical models in mice. 132 3

Most biliary tract cancers are advanced and inoperable when first diagnosed. Even if surgery can be performed, the postsurgical prognosis of these diseases is poor. In the present study, we investigated effective chemotherapies for a human bile duct cancer xenograft cell line (undifferentiated carcinoma, BDC-SN) and a gall bladder cancer xenograft cell line (well-differentiated adenocarcinoma, GBC-GN), which were transplanted into nude mice. Eight anticancer agents (CDDP, 5-FU, VDS, MMC, ADR, EPIR, CQ, and VP-16) and their various combinations were evaluated at 2-4 times the clinical dose. When used singly, CDDP, 5-FU, and VDS were effective against BDC-SN, and only CDDP was effective against GBC-GN. Among the various 2-agent combinations, CDDP + 5-FU was the most effective against both BDC-SN and GBC-GN. However, 3-agent combinations consisting of CDDP + 5-FU + another agent were less effective than the CDDP + 5-FU double regimen and caused significant loss of weight as well as high mortality. These results suggest that CDDP + 5-FU may be the most useful regimen against biliary tract cancers in clinical application.
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PMID:Experimental chemotherapy for xenograft cell lines of human bile duct and gall bladder cancers in nude mice. 143 61

A clear role for quinone reduction in the mechanism of action of doxorubicin has still to be established. There are three possible outcomes of this form of doxorubicin metabolism: (1) drug free radical formation, redox cycling and generation of reactive oxygen species (ROS) resulting in lipid peroxidation and DNA damage; (2) covalent binding of reactive drug intermediates to DNA; and (3) formation of an inactive 7-deoxyaglycone metabolite. In this work, the occurrence of each of these pathways has been studied in vivo in a subcutaneously growing rat mammary carcinoma (Sp 107). Doxorubicin was administered by direct intratumoural injection either as the free drug or incorporated in albumin microspheres (10-40 microns diameter). There was no evidence of an increase in lipid peroxidation over background after either treatment at any time point studied. In fact, doxorubicin administration resulted in a statistically significant reduction in lipid peroxidation at the later time points studied compared to control (no drug treatment), e.g. 24 hr: control, 21.7 +/- 2.8 SD nmol malondialdehyde/g tissue; free doxorubicin (70 micrograms drug), 14.5 +/- 4.0 SD nmol/g (P < 0.01 Student's t-test) and doxorubicin microspheres (70 micrograms drug), 17.4 +/- 1.1 nmol/g (P < 0.05). Covalent binding to DNA was measured by a 32P-post-labelling technique. Low levels of four putative drug-DNA adducts were detected; however, there were no qualitative or quantitative differences in profiles between free drug and microspheres. High 7-deoxyaglycone metabolite concentrations comparable to the parent drug itself were detected after administration of microspheres (3.0 micrograms/g +/- 1.7 SD at 24 hr and 3.1 micrograms/g +/- 1.1 SD at 48 hr). In contrast, these metabolites were present at levels close to the limit of detection of our HPLC assay after free drug (0.04 microgram/g +/- 0.03 SD at 24 hr and 0.02 microgram/g +/- 0.03 SD at 48 hr). Thus, 7-deoxyaglycone metabolite formation can occur in tumour tissue (indicating active drug quinone reduction) without concomitant increases in the level of lipid peroxidation or the levels of drug-DNA adducts. In conclusion, the main biological consequence of doxorubicin quinone reduction in vivo in tumour tissue would appear to be drug inactivation to a 7-deoxyaglycone metabolite rather than drug activation to DNA reactive species or ROS.
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PMID:The consequences of doxorubicin quinone reduction in vivo in tumour tissue. 147 81

We have reported previously that enzymes present in the Sp 107 rat mammary carcinoma catalyse doxorubicin quinone reduction (QR) to 7-deoxyaglycone metabolites in vivo [Willmott and Cummings, Biochem Pharmacol 36: 521-526, 1987]. In order to provide insights into the role of QR in the antitumour mechanism of action of doxorubicin, we have attempted in this work to identify the enzyme(s) responsible. NAD(P)H: (quinone acceptor) oxidoreductase (DT-diaphorase) was the major quinone reductase in the tumour accounting for approximately 70% of all the activity measured in microsomes and cytosols (microsomal activity, 28.4 +/- 4.6 nmol/min/mg; cytosolic activity, 94.3 +/- 11.9 nmol/min/mg). Its presence was confirmed by western blot analysis. Low levels of NADH cytochrome b5 reductase (15.6 +/- 6.3 nmol/min/mg) and NADPH cytochrome P450 reductase (14.5 +/- 4.0 nmol/min/mg) were detectable in microsomes. The presence of the latter was confirmed by western blot analysis. Pretreatment of tumours with doxorubicin (48 hr) at a therapeutic dose decreased the level of activity of all the reductases studied by at least 2-fold (P < 0.01, Student's t-test). Doxorubicin was shown not to be a substrate for purified rat Walker 256 tumour DT-diaphorase with either NADH or NADPH as co-factor and utilizing up to 20,000 units of enzyme/incubation but was confirmed to be a substrate for purified rat liver cytochrome P450 reductase. 7-Deoxyaglycone metabolite formation by purified cytochrome P450 reductase had an absolute requirement for NADPH as co-factor, was inhibited by molecular oxygen and dicoumarol (IC50 approx. 50 microM), and modulated by specific reductase antiserum. Reductive deglycoslation of doxorubicin to 7-deoxyaglycones was localized to the microsomal fraction of the Sp 107 tumour, with negligible activity being found in cytosols (NADH, NADPH and hypoxanthine as co-factors) and mitochondria (NADH and NADPH). The tumour microsomal enzyme had an absolute co-factor requirement for NADPH, was inhibited by oxygen and dicoumarol, and modulated by cytochrome P450 reductase antiserum. These data indicate strongly that NADPH cytochrome P450 reductase is the principal enzyme responsible for catalysing doxorubicin QR in the Sp 107 tumour.
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PMID:The enzymology of doxorubicin quinone reduction in tumour tissue. 147 82

Doxorubicin is one of the standard drugs in the chemotherapy of advanced urothelial tumors. Pirarubicin, a new anthracycline, turned out to be equally active and less toxic than its parent compound in preclinical studies. Twenty one patients with either metastatic or inoperable locally advanced bladder carcinoma were treated with intravenous infusion of pirarubicin: 25 mg/m2/day for 3 days every 4 weeks in the first 15 patients and 20 mg/m2/day for 3 days every 3 weeks in the others. Fifteen patients were not pretreated and 6 received prior chemotherapy (5 patients with doxorubicin containing regimen). Twenty patients were evaluable for response; there were 2 partial response, 8 stable disease and 10 progressive disease. All pretreated patients progressed. Hematological toxicity was moderate, however there was one toxic death with grade 4 neutropenia which occurred in a heavily pretreated patient receiving a dose of 25 mg/m2/day for 3 days. There was no clinical cardiac toxicity. Single agent Pirarubicin displays an objective response rate of 10% (95% of CI 0 to 23%) which reaches 14% (95% CI 0 to 29%) when non pretreated patients are analyzed separately. This rate is in the range of doxorubicin activity.
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PMID:Phase II trial of pirarubicin in the treatment of advanced bladder cancer. 148 7

Doxorubicin (Dox) was conjugated via a dextran linker to the F(ab')2 fragment of monoclonal antibody (MAb) 1H10 which recognizes an antigen expressed on the surface of human cervical carcinoma cells and tissues. Drug-antibody conjugates (1H10-Dox) with a molar ratio of Dox to MAb ranging from 40:1 to 60:1 retained antigen-binding and pharmacological activities. Anti-tumor activity of the conjugate in vitro was evaluated by measuring inhibition of [5-3H]-uridine incorporation into cellular RNA. 1H10-Dox was found to be 30 times more toxic to cervical tumor cells than a control MAb-Dox conjugate and 150 times more potent than Dox coupled to dextran. In addition, 1H10-Dox was less toxic to antigen-negative cells in vitro, suggesting that 1H10-Dox killing of cervical carcinoma cells was antibody-mediated. 125I-labeled 1H10-Dox preferentially localized in solid human cervical carcinoma xenografts in athymic mice with tumor-to-blood ratios of 1H10-Dox reaching 17.9 after 24 hr and 32.8 after 48 hr. Treatment of athymic mice bearing human cervical tumors with 1H10-Dox resulted in a dose-dependent inhibition of tumor growth. Multiple administrations of 1H10-Dox at a dose corresponding to 20 micrograms doxorubicin significantly suppressed the growth of human cervical tumors in nude mice without significant side effects (weight loss), and this suppression was antibody specific. Both i.p. and i.v. administration of 1H10-Dox were found to be equally effective. Our results suggest that 1H10-Dox may be useful for the treatment of human cervical carcinoma.
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PMID:Doxorubicin: monoclonal antibody conjugate for therapy of human cervical carcinoma. 156 95

Previous studies have demonstrated elevated levels of protein kinase C (PKC) activity in multidrug-resistant human breast carcinoma MCF-7/ADR cells compared to control drug-sensitive MCF-7/WT cells (R.L. Fine, J. Patel, and B.A. Chabner, Proc. Natl. Acad. Sci. USA, 85:582-586, 1988). In our present studies, immunohistochemical localization analysis using a polyclonal PKC antibody recognizing the alpha, beta, and gamma subtypes of PKC demonstrates that immunoreactivity is enhanced in MCF-7/ADR cells, with pronounced staining noted in the nuclear region. Other studies with purified nuclei isolated from MCF-7/ADR cells also show a marked increase in the intensity of immunostaining for PKC when compared to nuclei prepared from control MCF-7/WT cells. Western blot analysis of proteins extracted from purified nuclear preparations further establishes an increase in PKC enzyme protein associated with the nuclear fraction of MCF-7/ADR cells. Subcellular fractionation studies also indicate that MCF-7/ADR cells have 4-8 times higher nuclear PKC activity compared to that of control MCF-7/WT cells. MCF-7/ADR cells also possess 3-5-fold elevated cytosolic PKC activity, while a less than 2-fold increase is found in PKC activity associated with the plasma membrane fraction of MCF-7/ADR cells. Examination of these extracts with PKC isotype-specific antisera, as well as by DEAE-cellulose chromatography, reveals that nuclei prepared from MCF-7/ADR cells contain markedly elevated amounts of a slightly altered form of PKC alpha. These results suggest that elevated levels of a modified form of PKC alpha at the nucleus may play a role in modulating nuclear events to promote the development of multidrug resistance in MCF-7 cells.
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PMID:Elevated level of nuclear protein kinase C in multidrug-resistant MCF-7 human breast carcinoma cells. 161 46

We have investigated doxorubicin-induced lipid peroxidation by the measure of malondialdehyde (MDA) formation in rat glioblastoma cells and human breast carcinoma cells in culture. There was a significant production of MDA when the cells were incubated with pharmacologically relevant doxorubicin concentrations, i.e., concentrations that produce a significant cytotoxicity (0.1 micrograms/ml). At equitoxic doses, vincristine provided no lipid peroxidation, indicating that MDA formation is not a consequence of cell death. Doxorubicin-induced lipid peroxidation was maximal 24 h after incubation of the cells with doxorubicin, indicating that a delay was necessary for the free radical-mediated membrane damage induced by doxorubicin. In the presence of alpha-tocopherol in the culture medium, the doxorubicin-induced MDA formation was inhibited. The development of this method will help in defining the role of free radicals and lipid peroxidation in the cytotoxicity of doxorubicin.
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PMID:Measurement of doxorubicin-induced lipid peroxidation under the conditions that determine cytotoxicity in cultured tumor cells. 163 21

Cross-resistance to anticancer drugs, termed multidrug resistance (mdr), has been functionally associated with the expression of a plasma membrane energy-dependent efflux pump, termed P-glycoprotein, the product of the mdr1 gene. When MCF-7 breast carcinoma cells were transfected with the human mdr1 gene (BC-19 cells), they expressed levels of P-glycoprotein equivalent to those of cells selected for resistance to doxorubicin (MCF-7/ADR) but exhibited 10- to 50-fold less resistance to doxorubicin and vinblastine. We have now demonstrated that when BC-19 cells were stably transfected with protein kinase C alpha (PKC alpha), resistance to doxorubicin and vinblastine was increased; wild-type MCF-7 cells transfected with PKC alpha did not exhibit any change in drug resistance. Increased resistance in PKC alpha-transfected BC-19 cells was associated with enhanced PKC activity and phosphorylation of P-glycoprotein and decreased drug accumulation. The PKC activator, phorbol dibutyrate, further increased resistance to doxorubicin and stimulated P-glycoprotein phosphorylation. These results demonstrate that transfection of P-glycoprotein-expressing cells with PKC resulted in increased mdr and that PKC may have served as an important modulator of this process.
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PMID:Transfection with protein kinase C alpha confers increased multidrug resistance to MCF-7 cells expressing P-glycoprotein. 167 75

With the combination of pre- and postoperative chemotherapy and radiotherapy, the majority of patients with anaplastic giant cell thyroid carcinoma will achieve local tumor control. A few patients may even be cured by this treatment. Only few patients with differentiated thyroid carcinoma respond to chemotherapy treatment. However, at present it is not possible to discern these few. Chemotherapy for advanced thyroid carcinoma cannot as yet be routinely recommended. Doxorubicin, cisplatin, and VP16 are the drugs currently considered most effective. Side effects may be severe. Multimodality treatment may be an alternative.
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PMID:Chemotherapy and multimodality treatment in thyroid carcinoma. 169 85


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