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)

A new medium-term in vivo model was tried using pulmonary adenoma induced by benzo(a)pyrene (BP) in newborn mice. Both inbred mice such as C57BL/5J, C57BR/cdJ. A/J mice and non inbred N:GP(S) mice were used. Benzo(a)pyrene was injected in the subscapular region of newborn mice within 24 hours after birth at a dose of 0.5 mg and 1 mg per mouse, respectively. After 9 weeks lung tumor induced in N:GP(S) and A/J mice but in the other mice. The dose showing a 50% tumor incidence was found in N:GP(S) mice to be 0.5 mg of BP but the tumor incidence was very high in A/J mice even at 40 micrograms of BP, the lowest dose in this experiment. To verify the utility of this model, ascorbic acid, carrot, beta carotene, soybean lecithin, spinach, Sesamum indicum, Ganoderma lucidum, caffeine, red ginseng extract, fresh ginseng and 13-cis retinoic acid, some of which are known to have anticarcinogenic activity in various animal models, were tried with this system. Ascorbic acid, soybean lecithin, Ganoderma lucidum, caffeine and red ginseng extract showed inhibition of lung tumor incidence, while fresh ginseng, carrot, beta carotene, spinach and 13-cis retinoic acid did not. This result suggested that the 9-week medium-term model using lung tumor induced by 0.5 mg of BP was useful for the screening of cancer preventive agents.
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PMID:Trial of a new medium-term model using benzo(a)pyrene induced lung tumor in newborn mice. 764 68

Most drug discovery efforts have focused on finding new DNA-damaging agents to kill tumor cells preferentially. An alternative approach is to find ways to increase tumor-specific killing by modifying tumor-specific responses to that damage. In this report, we ask whether cells lacking the G1-S arrest in response to X-rays are more sensitive to X-ray damage when treated with agents that override G2-M arrest. Mouse embryonic fibroblasts genetically matched to be (+) or (-) p53 and rat embryonic fibroblasts (+) or (-) for wild-type p53 function were irradiated with and without caffeine, a known checkpoint inhibitor. At low doses (500 microM), caffeine caused selective radiosensitization in the p53(-) cells. At this low dose (where no effect was seen in p53(+) cells), the p53(-) cells showed a 50% reduction in the size of the G2-M arrest. At higher doses (2 mM caffeine), where sensitization was seen in both p53(+) and p53(-) cells, the radiosensitization and the G2-M override were more pronounced in the p53(-) cells. The greater caffeine-induced radiosensitization in p53(-) cells suggests that p53, already shown to control the G1-S checkpoint, may also influence aspects of G2-M arrest. These data indicate an opportunity for therapeutic gain by combining DNA-damaging agents with compounds that disrupt G2-M arrest in tumors lacking functional p53.
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PMID:Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. 771 68

We examined whether caffeine enhances the antitumor activity of adriamycin (ADR), in terms of prolonging survival in Ehrlich ascites carcinoma(ascites-type)-bearing mice. After administration of ADR at a dose of 0.5 mg/kg/d for 5d together with caffeine (100 mg/kg/d x 5 d), the survival period was increased by 39%. However, caffeine had little effect on this ADR induced-prolongation of survival following administration of ADR at 2.0 mg/kg/d for 4 d. Although a significant increase in ADR concentration in the ascites tumor was seen after administration of ADR at a dose of 0.5 mg/kg, caffeine failed to increase ADR concentration in the ascites tumor after administration of ADR at a dose of 2.0 mg/kg. The effect of caffeine thus appears to be due to its effect on the tumor distribution of ADR.
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PMID:Caffeine enhances adriamycin antitumor activity in Ehrlich ascites carcinoma-bearing mice. 773 32

We examined the effects of a combination of adriamycin (ADR) and caffeine on DNA and protein biosynthesis and on the activities of DNA polymerase alpha and beta in normal and tumor tissue. The decrease in DNA and protein biosynthesis in tumor produced by caffeine combined with ADR were 2.5 and 2.4 times greater, respectively, compared with ADR alone. The combination of caffeine and ADR enhanced the decrease in DNA polymerases activities in the tumor which was induced by ADR, the decreases being 1.8 and 1.6 times greater, respectively, than that of ADR alone. In contrast, these ADR-induced changes in normal tissues were not enhanced by the combination with caffeine. The combination with caffeine had no effect on ADR concentration in normal tissues, but in the tumor, it increased the ADR concentration to 2.1 times that of ADR alone. In vitro, ADR efflux from Ehrlich ascites carcinoma cells was significantly inhibited by exposure to caffeine. These findings indicate that the effect of caffeine on ADR concentration in the cell plays an important role in the mechanism by which caffeine enhances ADR antitumor activity.
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PMID:Mechanism of caffeine modulation of the antitumor activity of adriamycin. 786 36

The metabolic activation of food-borne heterocyclic amines to colon carcinogens in humans is hypothesized to occur via N-oxidation followed by O-acetylation to form the N-acetoxy arylamine that binds to DNA to give carcinogen-DNA adducts. These steps are catalyzed by hepatic cytochrome P4501A2 (CYP1A2) and acetyltransferase-2 (NAT-2), respectively, which are known to be polymorphic in humans. On the basis of this proposed metabolic activation pathway, patients at greatest risk to develop colorectal cancer or nonfamilial polyps should be those who possess both the rapid NAT-2 and rapid CYP1A2 phenotypes and are exposed to high dietary levels of carcinogenic heterocyclic amines. Using a method that involves caffeine administration and high pressure liquid chromatographic analysis of urinary metabolites, we have determined the CYP1A2 and NAT-2 phenotypes of 205 controls and 75 cancer/polyp cases. Exposure information was obtained using a dietary and health habits questionnaire. Both the rapid CYP1A2 and rapid NAT2 phenotypes were each slightly more prevalent in cases versus controls (57% and 52% versus 41% and 45%, respectively). However, the combined rapid CYP1A2-rapid NAT-2 phenotype was found in 35% of cases and only 16% of the controls, giving an odds ratio of 2.79 (P = 0.002). Univariate analysis of the questionnaire indicated that age, rapid-rapid phenotype, and consumption of well done red meat were associated with increased risk of colorectal neoplasia. Furthermore, a logistic regression model that included age (as a continuous variable), consumption of well done red meat, and rapid-rapid phenotype as independent covariates gave odds ratios of 1.08, 2.08, and 2.91, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne heterocyclic amines increase the risk for colorectal cancer or polyps. 788 41

Expression of the recombination activating genes, RAG-1 and RAG-2, in lymphocytes, has been shown to depend on second messenger systems. An increase in intracellular cAMP upon stimulation with caffeine increases RAG expression while activation of protein kinase C (PKC) with phorbol myristate acetate (PMA) results in decreased RAG expression. The stringent regulation of recombination appears to be partially dependent on protein kinase activities which, alone, are not likely to be sufficient to regulate recombinase activity. We provide evidence implicating a role for serine/threonine phosphatases in the signal transduction pathway which regulates RAG gene expression and consequently the recombination process in lymphocytes. The cell permeable tumor promoter, calyculin-A (CLA), which is a potent inhibitor of the type 1 and 2A serine/threonine protein phosphatases (PP1 and PP2A, respectively), was shown to upregulate the expression of RAG-1 and RAG-2 in pre-B as well as mature B- and T-lymphocyte cell lines. Although agents such as caffeine known to increase intracellular cAMP levels induce RAG expression, synergy between CLA and caffeine was not detected in pre-B cells. An in vivo assessment of recombination activity after transfection of pre-B cells with an extrachromosomal recombination vector revealed a moderate increase in recombinase activity which paralleled RAG expression after CLA stimulation. Although increased cAMP levels in pre-B cells has been associated with upregulation of RAG expression we found no such upregulation in a surface immunoglobulin M positive (sIgM+) cell line, WEHI-231, and a T cell receptor positive (TCR+) murine cell line, EL-4. Moreover, in these mature lymphocyte cell lines there was no evidence of synergy in the regulation of RAG-1 and RAG-2 mRNA upon stimulation with CLA and caffeine. These results suggest novel intracellular mechanisms for the upregulation of RAG gene expression and confirm a role for type 1 and 2A phosphatases in the control of RAG gene expression and recombinase activity in lymphocyte cell lines.
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PMID:RAG-1 and RAG-2 gene expression and V(D)J recombinase activity are enhanced by protein phosphatase 1 and 2A inhibition in lymphocyte cell lines. 789 93

The goal of these experiments was to investigate further the relationship between DNA double-strand breaks and cell killing in human tumor cells, first by comparing different cell lines, and second by radiomodification studies. Field-inversion gel electrophoresis was used to quantify double-strand breaks. Two subclones of the radioresistant human squamous cell carcinoma line SQ20B (SQD9 and SQG6) were compared. These subclones differed in DNA index by a factor of 1.7 but showed the same resistance to radiation as cells of the parental cell line. It was found that, although induction of DSBs was not significantly different in the two cell lines, the t1/2 of the fast component of repair was significantly shorter for SQD9 cells, leading to greater overall repair which was not reflected in increased survival. Caffeine and cysteamine were tested as modifiers of radiosensitivity, using the radioresistant SQ20B line and the radiosensitive SCC61 cell line. No effect of caffeine was seen when the drug was present only during irradiation. Postirradiation incubations with caffeine, however, resulted in a dose reduction factor greater than 2.0 in cell survival for both cell lines. In contrast, induction of DSBs was reduced by caffeine, and no effect on DSB repair was observed. Cysteamine led to a dose protection factor greater than 1.8 in cell survival in both cell lines. A reduction in induced DSBs was found at high doses corresponding approximately with the increase in cell survival. Over the same (low) dose range, however, the correlation between DSB induction and cell killing was poor. These data indicate that DSB induction does not correlate well with cell killing either for different cell lines, for radiochemical modification (cysteamine) or for some other types of modification (caffeine).
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PMID:Differential repair of radiation-induced DNA damage in cells of human squamous cell carcinoma and the effect of caffeine and cysteamine on induction and repair of DNA double-strand breaks. 793 62

The effect of caffeine, the methylated xanthine, in sensitizing the lethal action of ionizing radiation in vitro was investigated in human cancer cells which were clinically known to be radioincurable. The tumor lines were hepatocellular carcinoma and colon adenocarcinoma. Plateau phase cultures, after absorbing doses of 2 Gy, survived at a rate of 56.30 per cent for colon cancer and at 66.05 per cent for liver cancer. Both lines were radiosensitized by caffeine but at different potencies. Noteworthily, hepatocellular carcinoma whilst less radiosensitive than colon adenocarcinoma was 4 times more susceptible to caffeine. The lowest effective caffeine concentration for liver cancer was 2 mM which slightly exceeded the anticipated lethal concentration in humans. Research on radiosensitizing effect of methylated xanthines on hepatoma system still remains intriguing. Future work should be pursued with the use of less toxic compounds, such as theobromine.
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PMID:Differential radiosensitization of radioresistant human cancer cells by caffeine. 800 58

We investigated the effect of DNA-repair-enzyme inhibitors on L-phenylalanine mustard (L-PAM) and cis-diamminedichloroplatinum (II) (CDDP) cytotoxicity in rat mammary-carcinoma MatB cells sensitive (WT) and resistant (MLNr) to bifunctional alkylating drugs. Among the modulators tested, the combination of arabinofuranosylcytosine (Ara-C) and hydroxyurea (HU) significantly increased the sensitivity of the cells to CDDP and, to a lesser extent, L-PAM as compared with cells treated with drug alone. The modulation effect of HU+Ara-C on CDDP and L-PAM cytotoxicity was more effective when intracellular glutathione (GSH) was depleted by L-buthionine-(S,R)-sulfoximine (BSO). This was also associated with a significant increase in DNA-DNA interstrand cross-links. Caffeine also sensitized both WT and MLNr cells to the cytotoxic effect of L-PAM and CDDP, and this effect was potentiated in GSH-depleted cells. No significant effect was observed with other repair modulators such as aphidicolin, 3-aminobenzamide, novobiocin, or etoposide. These results show (a) that inhibition of DNA repair by HU+Ara-C or caffeine could be a target for modulation of bifunctional alkylating-drug resistance and (b) that GSH depletion renders resistant cells more susceptible to the repair-enzyme modulators, suggesting that intracellular GSH may be involved in the regulation of some of these enzymes. Our results also indicate that a combination of a number of modulators may offer an advantage over the use of a single modulator in tumor resistance that may be associated with multifactorial mechanisms.
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PMID:Effect of DNA-repair-enzyme modulators on cytotoxicity of L-phenylalanine mustard and cis-diamminedichloroplatinum (II) in mammary carcinoma cells resistant to alkylating drugs. 819 66

Recent advances in adjuvant chemotherapy for malignant bone tumor have been improving the survival rate and making limb-salvage surgery a reliable technique. Ewing's sarcoma is treated by multiple agent chemotherapy. We treat Ewing's sarcoma by Rosen's T-11 protocol (CYT.ADM.MTX.VCR.ACT-D.BLM). This protocol is very effective, but results are poorer than for osteosarcoma. Newly developed protocols such as EICESS (European Intergroup Cooperative Ewing's Sarcoma Study)-92, including new drugs, should be investigated. The results with malignant fibrous histiocytoma are comparable to those for osteosarcoma. We have performed an original chemotherapy protocol, called "K-1 protocol." Patients were treated with three courses of intraarterial infusion of cisplatin (120 mg/m2) and caffeine (1.0-1.5 mg/m2/day for three days continuously) at two-week intervals. If the effect was insufficient, ADM (30 mg/m2/day for two days continuously) is added to this protocol. We treat malignant lymphoma in collaboration with a hematologist and radiologist. The 5-year survival rate of non-Hodgkin's lymphoma in our series was 56% in clinical stage III and 34% in clinical stage IV. We are trying third-generation chemotherapy to improve the survival rate.
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PMID:[Chemotherapy for Ewing's sarcoma, malignant fibrous histiocytoma and malignant lymphoma]. 821 63


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