Studies on the mechanism by which indomethacin increases the anticancer effect of methotrexate

Bennett, A. B.; Gaffen, John D.; Melhuish, P B; Stamford, I F

doi:10.1111/j.1476-5381.1987.tb09003.x

Cited by 26 publications

(21 citation statements)

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“…Synergistic effects were reported as early as in the 1980s. The combination of indomethacin with methotrexate increased the killing of cultured NC cells without providing an exhaustive mechanism for this effect (Bennett et al, 1987). More recently, a report performed the first extensive screen of commercially available NSAIDs with anticancer drugs and discussed the potential clinical benefits of such a combination (Duffy et al, 1998); the authors observed dose-dependent synergistic effects among the two classes of drugs and concluded that this effect occurred independently from COX inhibition.…”

Section: Common Death Pathways Between Nsaids and Anticancer Drugsmentioning

confidence: 99%

Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy

et al. 2003

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In this review, we discuss the available experimental evidences supporting the chemopreventive efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) on colorectal cancer and the biological basis for their possible role as anticancer agents. Although the comprehension of the mechanisms underlying the effects of these drugs on colon cancer cells is incomplete, research efforts in identifying the biochemical pathway by which NSAIDs exert their chemopreventive effect have provided a rationale for the potential use of NSAIDs alone or in combination with conventional and experimental anticancer agents in the treatment of colorectal cancer. In this paper, we review three main issues: (i) the role of COX-2 in colon cancer; (ii) the common death pathways between NSAIDs and anticancer drugs; and (iii) the biological basis for the combination therapy with COX-2 selective inhibitors and new selective inhibitors of growth factor signal transduction pathways. ROLE OF COX-2 IN COLON CANCERColorectal cancer is the third most common cancer in the world, and the second most common cause of cancer-related death. Despite the development of new strategies of aggressive surgical and adjuvant therapy, little progress has been made in the successful management of advanced disease; therefore, much hope is currently placed on chemoprevention.A large body of evidence from epidemiological studies and clinical trials in patients with the hereditary colon cancer syndrome, familial adenomatous polyposis coli (FAP) indicates that aspirin and related drugs, known as nonsteroidal antiinflammatory drugs (NSAIDs), which share the property of inhibiting the cyclooxygenase (COX) enzyme, hinder the development of colon cancer and perhaps other cancers as well.COX is the rate-limiting enzyme for the synthesis of eicosanoids, such as prostaglandins, from arachidonic acid. Two COX isoforms have been identified: the constitutively expressed COX-1 and the inducible COX-2. COX-1 is a housekeeping gene and has an important role in protecting the gastroduodenal mucosa. The COX-2 gene, an immediate-early response gene, is rapidly induced in response to tumour promoters, cytokines, and growth factors Di Popolo et al, 2000). NSAIDs may achieve different degrees of inhibition of COX-1 and COX-2 and can be grouped into selective and nonselective inhibitors of COX-2.The development of COX-2-specific inhibitors, like celecoxib and rofecoxib, drugs that maintain their anti-inflammatory properties while preserving the biosynthesis of protective prostaglandins, further raised interest in this field. A large body of research was therefore performed to clarify the relative involvement of the two COX isoforms in colorectal carcinogenesis and the role of COX-2-selective inhibitors as chemopreventive agents.COX-2, but not COX-1, expression was found to be increased in colorectal cancer (Eberhart et al, 1994): approximately 50% of adenomas and 80 -85% of adenocarcinomas showed increased expression of COX-2. This observation was later confirmed by other investigators. Mo...

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Section: Common Death Pathways Between Nsaids and Anticancer Drugsmentioning

confidence: 99%

Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy

et al. 2003

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“…Our previous results in vitro indicate that the effect does not involve MTX displacement from binding sites on serum proteins, or inhibition of prostaglandin formation, cAMP phosphodiesterase or of calcium transport (Gaffen et al, 1985(Gaffen et al, , 1989Bennett et al, 1987;Gaffen et al, 1991). However, inhibition of prostaglandin synthesis seems to explain the prolongation of survival by INDO in NC tumour-bearing mice , and we have not excluded the possibility that this mechanisms may contribute to the potentiation of MTX cytotoxicity in vivo.…”

Section: Discussionmentioning

confidence: 97%

“…Methotrexate/indomethacin interaction The MTX/INDO interaction is important because INDO potentiates both the MTX-induced prolongation of survival of mice with NC tumours, and the killing of NC cells and human breast cancer cells in culture (Bennett et al, 1987). The mechanism(s) are not fully understood, but we recently found that INDO potentiated the changes in FA composition induced by MTX in cultured NC cells (Soydan et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…We then demonstrated that INDO potentiates the anticancer effect of MTX in vitro and in vivo. The mechanism is not clear, but the effect in vitro probably does not involve MTX displacement from binding sites on serum proteins, or inhibition of prostaglandin formation, cAMP phosphodiesterase or of calcium transport (Gaffen et al, 1985(Gaffen et al, , 1989Bennett et al, 1987;Gaffen et al, 1991). Possibilities examined in the present study are whether INDO and MTX alone and together affect the fatty acids (FAs) of malignant and 'normal' tissues, and whether the potentiation of MTX cytotoxicity involves alteration of tumour FA composition.…”

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confidence: 96%

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Changes in tissue fatty acid composition in murine malignancy and following anticancer therapy

Yazıcı

Tavares²,

Stamford³

et al. 1992

Br J Cancer

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Summary We studied the mouse NC tumour, a subcutaneously transplanted adenocarcinoma originally of mammary origin. Measurements per g tissue were made of 17 fatty acids (FAs), the combined amounts of n-3, n-6, saturated, unsaturated, and total FAs, and of various FA ratios in the tumour, mammary tissue, spleen, liver and plasma. Compared with mammary tissue from normal mice, tumours of vehicle-treated controls had less of seven of the FAs and more of two FAs. Mice bearing the NC tumour often had changed (usually decreased) amounts of FAs in the 'normal' spleen, liver and plasma, but not in mammary tissue. Treatment with methotrexate (MTX) was studied alone and with indomethacin which can potentiate MTX cytotoxicity. Indomethacin 1.25 mg kg-' (INDO) increased the amounts of 3/17 tumour FAs and the unsaturated FAs, but reduced 9/17 FAs, the saturated and the unsaturated FAs in 'normal' mammary tissue, and usually had no effect on the FAs of other tissues. MTX 2 or 4 mg kg-' (MTX 2 or 4 mg) ± INDO in general partly restored (increased) the amounts of tumour FAs, and reduced the saturated/unsaturated FA ratio. In the 'normal' spleen and plasma also, but not in the liver, MTX 2 mg generally somewhat restored the FA composition. However, as in the liver, the spleen 20:4 and 22:6 (which form prostaglandins and lipid peroxides) did not increase in the presence of INDO. With MTX 4 mg, some of the plasma and liver FAs decreased, in contrast to the tumour. There was generally no evidence of MTX potentiation by INDO. These results are discussed in relation to carcinogenesis, cachexia, and the response to treatment.

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“…Non-steroidal antiinflammatory drugs (NSAIDs) inhibit the COX-2 enzyme activity. Several preclinical and clinical studies have shown that NSAIDs are effective chemopreve ntive and antitumor agents either alone or in combination with standard cancer therapies [5][6][7]. Previously it was shown that NSAIDs, indomethacin and NS-398, applied in low dose effectively increased the 5-fluorouracil (5-FU)-sensitivity in high COX-2 protein-expressing HCA-7 colon cancer cells [8].…”

Section: Introductionmentioning

confidence: 99%

Enhanced 5-fluorouracil cytotoxicity in high cyclooxygenase-2 expressing colorectal cancer cells and xenografts induced by non-steroidal anti-inflammatory drugs via downregulation of dihydropyrimidine dehydrogenase

Réti

Pap

Adleff

et al. 2009

Cancer Chemother Pharmacol

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Studies on the mechanism by which indomethacin increases the anticancer effect of methotrexate

Abstract: 1The effect of indomethacin on the response of the NC carcinoma to methotrexate has been examined in vivo and in vitro.

Cited by 26 publications

References 14 publications

Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy

Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy

Changes in tissue fatty acid composition in murine malignancy and following anticancer therapy

Enhanced 5-fluorouracil cytotoxicity in high cyclooxygenase-2 expressing colorectal cancer cells and xenografts induced by non-steroidal anti-inflammatory drugs via downregulation of dihydropyrimidine dehydrogenase

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