Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Posttreatment incubation with nontoxic doses of caffeine resulted in enhancement of cell lethality and inhibition of cell growth in L1210 mouse leukemia cells which had been exposed to a protein antibiotic, neocarzinostatin. In addition, caffeine treatment appeared to inhibit the eventual maturation of newly synthesized DNA in L1210 cells following exposure to this antibiotic. These results, indicating the existence of caffeine-sensitive repair in L1210 leukemia cells treated with neocarzinostatin, provide further evidence for DNA damage as a mechanism of the cytocidal action of the antibiotic.
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PMID:Enhancement by caffeine of neocarzinostatin cytotoxicity in murine leukemia L1210 cells. 15 73

Certain psychotropic drugs when combined with caffeine significantly enhanced the antitumor effect of 1,3-bis(2-chloroethyl)-1-nitrosourea in murine leukemia L1210. Enhancement required that all three drugs be given together and optimal results were obtained when the psychotropic drug was given 6 hours before 1,3-bis(2-chloroethyl)-1-nitrosourea and caffeine. Thus, 1,3-bis(2-chloroethyl)-1-nitrosourea alone or with caffeine resulted in 5% cures. Addition of chlorpromazine increased the cure rate to 51% while prochlorperazine gave 30% cures. Chlordiazepoxide produced 39% cures while the dibenzazepine compounds studied were ineffective. For the phenothiazine, benzodiazepine and dibenzazepine compounds studied, tentative conclusions could be drawn on the relationship of chemical structure to enhancing activity. For phenothiazines, the substituent in the R2 position of the phenothiazine ring determined activity to a greater extent than did the substituent in the R1 position. For the benzodiazepine compounds, chlordiazepoxide was superior to diazepam. Although the mechanism of action of psychotropic drugs in this system is unknown, these preliminary results suggest the possibility of a change transfer reaction between the free radical form of the psychotropic drug and one or more intracellular constituents.
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PMID:Enhancement of the antitumor effect of 1,3-bis(2-chloroethyl)-1-nitrosourea by various psychotropic drugs in combination with caffeine. 24 17

The therapeutic usefulness of chlorpromazine (CPZ) and caffeine (CAF) in combination with selected nitrosoureas was investigated in mice bearing L1210 leukemia, Lewis lung carcinoma, and B16 melanoma. We found that using BCNU with either CAF or CPZ was therapeutically superior to using either agent alone to treat mice bearing L1210 leukemia. Administering all three drugs in combination did not improve upon the therapeutic responses obtained with the two-drug combinations. In mice implanted with Lewis lung carcinoma or B16 melanoma, responses to treatment with the triple combination of methyl-CCNU, CAF, and CPZ suggested, but did not clearly establish, superiority over each two-drug combination or methyl-CCNU alone.
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PMID:Therapeutic potentiation of nitrosoureas using chlorpromazine and caffeine in the treatment of murine tumors. 75 16

The enhanced effect of CDDP combined with caffeine against P-388 leukemia was investigated. No synergistic effect was shown after one hour simultaneous treatment with CDDP and caffeine. But the growth inhibition was enhanced by the addition of caffeine after one hour treatment with CDDP. It is suggested that caffeine inhibits DNA repair by the reduction of CDDP-induced elongation of G2 + M phase. The increase in life span of mice after ip transplantation was observed by frequent ip injections of caffeine after CDDP injection. It is suggested that the effect of intraperitoneal administration of CDDP against peritoneal metastasis is enhanced by combination with caffeine.
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PMID:[Enhanced effect of intraperitoneal administration of CDDP combined with caffeine against peritoneal metastasis]. 187 25

The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of ML-1 myeloblastic leukemia cells to nonlethal doses of the DNA damaging agents, gamma-irradiation or actinomycin D, causes a transient inhibition of replicative DNA synthesis via both G1 and G2 arrests. Levels of p53 protein in ML-1 cells and in proliferating normal bone marrow myeloid progenitor cells increase and decrease in temporal association with the G1 arrest. In contrast, the S-phase arrest of ML-1 cells caused by exposure to the anti-metabolite, cytosine arabinoside, which does not directly damage DNA, is not associated with a significant change in p53 protein levels. Caffeine treatment blocks both the G1 arrest and the induction of p53 protein after gamma-irradiation, thus suggesting that blocking the induction of p53 protein may contribute to the previously observed effects of caffeine on cell cycle changes after DNA damage. Unlike ML-1 cells and normal bone marrow myeloid progenitor cells, hematopoietic cells that either lack p53 gene expression or overexpress a mutant form of the p53 gene do not exhibit a G1 arrest after gamma-irradiation; however, the G2 arrest is unaffected by the status of the p53 gene. These results suggest a role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage and thus suggest a new mechanism for how the loss of wild-type p53 might contribute to tumorigenesis.
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PMID:Participation of p53 protein in the cellular response to DNA damage. 2737 38

The thymidine kinase-deficient subclone, 707BUF, of the Friend murine leukaemia cell line exhibits increased sensitivity to the induction of cytogenetic aberrations by mitomycin C (MMC) relative to wild-type clone 707. It has been suggested that thymidine kinase-deficient cells may be highly mutagen-sensitive through an imbalance of nucleotide pools rendering excision repair error-prone. In this study clone 707 Friend leukaemia cells were compared with subclone 707BUF for sensitivity to the potentiating effect of caffeine on MMC-induced cytogenetic aberrations. The results indicate that although potentiation of mitomycin C-induced cytogenetic damage occurs in both clone 707 and in subclone 707BUF following caffeine treatment, the mutagen-sensitive thymidine kinase-deficient subclone 707BUF had enhanced potentiation by caffeine of MMC-induced cytogenetic damage relative to wild-type clone 707. It is suggested that caffeine may enhance mutagen sensitivity by inhibiting post-replication repair processes and may perhaps also indirectly reduce the effectiveness of the excision repair system by inhibiting the mutagen-induced G2-delay. Clone 707 wild-type cells in the presence of caffeine could then continue to repair DNA damage through an intact though less effective excision repair system, whilst the thymidine kinase-deficient subclone 707BUF would, in the presence of caffeine, be rendered highly mutagen sensitive, being only able to repair DNA damage through an error-prone excision repair process.
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PMID:Enhanced synergism between caffeine and mitomycin C in the induction of cytogenetic aberrations in thymidine kinase-deficient Friend murine erythroleukaemia cells. 313 10

Inhibitors of poly(ADP-ribose) polymerase show a synergistic potentiation of cytotoxicity with certain DNA-damaging agents. Non-toxic concentrations of 5-methylnicotinamide dramatically potentiate the cytotoxicity of N-methyl-N-nitrosourea as tested by the cloning ability of mouse leukaemia (L1210) cells. A dose-enhancement factor of about 10 is observed. This potentiation is dependent on the concentration of 5-methylnicotinamide. The methylxanthines theobromine, theophylline and caffeine also increase the cytotoxicity of methylnitrosourea. Thymidine, in the presence of sufficient deoxycytidine to overcome the perturbation of deoxynucleotide metabolism, also potentiates the cytotoxicity of methylnitrosourea. Nicotinate, which is not an inhibitor of poly-(ADP-ribose) polymerase, has no effect on methylnitrosourea toxicity. A very small, but consistent, enhancement of the toxicity of gamma-radiation by the same inhibitors has been observed. We suggest that this potentiation of cytotoxicity is mediated by inhibition of (ADP-ribose)n biosynthesis; and that the biosynthesis is stimulated by DNA damage. We therefore propose that (ADP-ribose)n takes part in cellular repair mechanisms, either by modifying chromatin structure or by a specific participation in DNA repair.
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PMID:The enhancement of cytotoxicity of N-methyl-N-nitrosourea and of gamma-radiation by inhibitors of poly(ADP-ribose) polymerase. 624 84

The effect of exposing mice to both a chemical carcinogen and leukemia virus with and without an inhibitor of DNA repair were compared. The data indicated that benzo[a]pyrene (BP) could exert a potentiating effect of Friend viral leukemogenesis in mice, which was dependent on the relative times of administration of the chemical and virus. The addition of caffeine as an inhibitor of DNA repair further enhanced the potentiating effect of BP on the leukemia, but in the absence of BP, caffeine showed no carcinogenic effect either when given alone or in conjunction with Friend leukemia virus.
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PMID:Potentiating effect of benzo[a]pyrene and caffeine on Friend viral leukemogenesis. 626 20

The present study was designed to elucidate the cytotoxic potential of 8 possible substituted uracilic metabolites of methylxanthines. 5-Fluorouracil (5-FU) was used as a reference uracil analogue with cytotoxic activity. Substituted uracil derivatives examined in this study did not affect the proliferative capacity of PHA-stimulated rat lymphocytes, murine L1210 leukaemia and rat chondrocytes. Caffeine had some growth inhibitory activity of extremely high concentrations (greater than 100 micrograms/ml). In vivo administration of 6-amino-5[N-methyl-formylamino]1,3-dimethyluracil (1,3,7-TAU) and 6-amino-5[N-acetylamino]3-methyluracil (7-A3-MAU) caused a transient short-lived reduction of L1210 tumour cell numbers. These observations do not appear to support the hypothesis that substituted uracils are involved in the toxicity of high doses of caffeine in rats.
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PMID:In vitro and in vivo cytotoxicity of possible uracil metabolites of methylxanthines. 662 37

One hundred and fifty-seven evaluable patients with advanced metastatic malignant melanoma were randomly assigned to receive either methyl-CCNU (MeCCNU) (200 mg/m2 orally every 6 weeks) (82 patients) or a combination of MeCCNU, chlorpromazine (50 mg/m2 im), and caffeine (600 mg/m2 sc) in the periumbilical area (75 patients). The response rate was 12% for the combination (three complete responses and six partial responses) and 11% for MeCCNU alone (two complete responses and seven partial responses). The median survival was 20 weeks and was the same for both treatments. The data support the hypothesis that caffeine and chlorpromazine do not enhance MeCCNU activity in malignant melanoma, unlike the marked enhancement seen for this drug combination in L1210 leukemia in mice.
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PMID:Randomized trial of chlorpromazine, caffeine, and methyl-CCNU in disseminated melanoma. 699 Nov 2


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