Treatment of mouse carcinoma in vivo with a prostaglandin E2 analogue and indomethacin

Bennett, A. B.; Carroll, Mairéad A.; Melhuish, P B; Stamford, I F

doi:10.1038/bjc.1985.184

Cited by 27 publications

(9 citation statements)

References 20 publications

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“…As we have previously reported (Bennett et al, 1982(Bennett et al, , 1985, indomethacin, flurbiprofen, or methotrexate + melphalan prolong the survival of mice with excised transplanted NC tumours. This prolongation is greater when indomethacin or flurbiprofen are given together with the cytotoxic drugs.…”

Section: Discussionsupporting

confidence: 55%

“…Dazmegrel given alone or with methotrexate + melphalan did not alter mouse survival. Apart from the lack of effect on tumour thromboxane synthesis, no alteration of survival would necessarily be anticipated with a thromboxane synthesis inhibitor since the prolongation with indomethacin seems to be prostaglandinmediated; the effect of indomethacin was counteracted by giving a long-acting PGE2 analogue (Bennett et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

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Survival of mice with NC carcinoma is unchanged by drugs that are thought to inhibit thromboxane synthesis or increase prostacyclin formation

Stamford¹,

Melhuish²,

Carroll³

et al. 1986

Br J Cancer

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Summary Mice transplanted with NC carcinoma were treated with the thromboxane synthetase inhibitor dazmegrel (UK38485) or with nafazatrom (BAY G 6575), a compound that is reported to increase prostacyclin formation. Some experiments included the cytotoxic drugs methotrexate and melphalan. The tumours were excised under anaesthesia on day 14 or day 21 after transplanation, and weighed; some were extracted for prostanoids which were measured by radioimmunoassay. Mouse survival time was determined up to day 121, and cancer spread was determined by postmortem examination. The survival was increased by methotrexate and melphalan but not by the other drugs. Nafazatrom-treated mice tended to have lighter tumours. Although dazmegrel reduced the formation of thromboxane B2 during clotting of blood from normal mice, it did not affect the tumour yields of prostanoids. Nafazatrom had no effect on serum or tumour prostanoids. There were no obvious effects of the treatments on the recurrence of tumour in the excision scar, lung metastasis or spread to lymph nodes.Effects of the arachidonate metabolites thromboxane A2 (TXA2) and prostacyclin (PGI2) on platelet aggregation are well known. The ability of TXA2 produced by platelets to cause their aggregation may normally be balanced by PGI2 which is inhibitory (Moncada & Vane, 1979). Platelet aggregation is thought to be important in the haematogenous spread of some tumours, and Honn (1982) and his colleagues (Honn et al., 1981(Honn et al., , 1983 suggested that circulating tumour cells, or vesicles shed from the primary tumour cells, disrupt the balance between PGI2 and TXA2 in favour of platelet aggregation. Experiments with intravenously injected B-16a melanoma cells showed that thromboxane synthesis inhibitors, PGI2, or nafazatrom (which has various actions including an increase of PGI2 formation), are antimetastatic (Honn, 1982;Honn et al., 1983). A thromboxane synthesis inhibitor also reduced spontaneous metastasis from Lewis lung carcinoma (Honn, 1982 Drugs that inhibit cyclo-oxygenase usually reduce the size of NC tumours, and prolong host survival when given alone or with the cytotoxic drugs methotrexate and melphalan (Bennett et al., 1979(Bennett et al., , 1982. Cyclo-oxygenase inhibitors reduce both thromboxane and prostaglandin formation, but it is not known if the effect on thromboxane production contributes to the effects of indomethacin and flurbiprofen on tumour size and mouse survival.The aims of the present study were: (i) to examine Honn's hypothesis, using nafazatrom or the thromboxane synthetase inhibitor dazmegrel in the mouse NC tumour model, (ii) to measure mouse survival time, tumour weight and prostanoid content and (iii) to study the effect of dazmegrel in combination with cytotoxic drugs. Materials and methodsThe NC carcinoma used in these studies originally arose spontaneously in the mammary region of a WHT/Ht mouse (Hewitt et al., 1976), the same strain used in our experiments. Following local excision of this carcinoma there is a high incidence of l...

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Survival of mice with NC carcinoma is unchanged by drugs that are thought to inhibit thromboxane synthesis or increase prostacyclin formation

Stamford¹,

Melhuish²,

Carroll³

et al. 1986

Br J Cancer

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“…Lynch et al (1978) found that indomethacin, aspirin or hydrocortisone increased the survival of mice with methylcholanthrene-induced tumours, although only the nonsteroids significantly reduced the tumour size. Inhibition of prostaglandin synthesis appears to explain the antitumour effect of indomethacin on the NC cancer, since a stable PGE2 analogue counteracted the increase in survival (Bennett et al, 1985). However, in the present experiments prednisolone or mepacrine had little or no effect on the cancer or its response to the cytotoxic drugs.…”

Section: Discussioncontrasting

confidence: 52%

“…Survival is even longer when these nonsteroidal anti-inflammatory drugs are used with the cytotoxic drugs methotrexate and melphalan . The effects of the anti-inflammatory drugs seems likely to result from inhibition of prostaglandin synthesis rather than from other properties that the drugs may have (Flower, 1974), since administration of a PGE2 analogue counteracted the effect of indomethacin (Bennett et al, (1985). A similar effect might therefore be expected with other drugs that reduce prostaglandin formation, such as corticosteroids and mepacrine which can inhibit phospholipase activity and so depress the release of prostaglandin precursors (Vane et al, 1982).…”

mentioning

confidence: 99%

Cancer in mice: effects of prednisolone or mepacrine alone and with cytotoxic drugs

Bennett¹,

Melhuish²,

Patel³

et al. 1987

Br J Cancer

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Summary WHT/Ht mice were transplanted s.c. with NC carcinoma, and the tumours were excised after 2 weeks. The mice were treated orally throughout the experiments with prednisolone 500pgkg-' or mepacrine 3.6mg kg-1, starting the day after tumour transplantation or, with prednisolone, the day after tumour excision. In some experiments the mice were also treated with the cytotoxic drugs methotrexate 2mg kg 1 and melphalan 1.4mgkg-1. The excised tumours were weighed; some of them, and samples of serum, were extracted for prostanoids which were measured by radioimmunoassay. The chemotherapy lengthened the survival of the mice, but prednisolone or mepacrine had little or no effect on survival, metastasis, the response to chemotherapy, tumour size or the formation of tumour prostanoids.Prostaglandin synthesis inhibitors have been extensively investigated in various murine cancers, and they usually show a beneficial effect (Bennett, 1982;1986). In the NC tumour model the prostaglandin synthesis inhibitors indomethacin or flurbiprofen increase mouse survival and usually reduce tumour size. Survival is even longer when these nonsteroidal anti-inflammatory drugs are used with the cytotoxic drugs methotrexate and melphalan . The effects of the anti-inflammatory drugs seems likely to result from inhibition of prostaglandin synthesis rather than from other properties that the drugs may have (Flower, 1974), since administration of a PGE2 analogue counteracted the effect of indomethacin (Bennett et al., (1985). A similar effect might therefore be expected with other drugs that reduce prostaglandin formation, such as corticosteroids and mepacrine which can inhibit phospholipase activity and so depress the release of prostaglandin precursors (Vane et al., 1982). This action may be particularly relevant to human cancers since prednisolone is frequently used in chemotherapy regimens. We have therefore studied the effects of prednisolone and mepacrine, alone and in combination with the cytotoxic drugs methotrexate and melphalan, in mice with NC tumours. Measurements were made of tumour weight and prostanoid content, the occurrence of metastases, and mouse survival. Materials and methodsThe original NC tumour arose spontaneously in the mammary region of a WHT/Ht mouse (Hewitt et al., 1976) and has since been passaged only in this strain. It has a high incidence of local lymphatic spread, recurrence in the scar following tumour excision, and metastasis mainly to the lungs and mediastinum.On day 0, male or female WHT/Ht mice were injected s.c. into the left flank with -106 NC carcinoma cells in a singlecell suspension from passaged tumours as described previously (Bennett et al., 1979. All tumours were excised at 2 weeks and weighed. The study consisted of 6 separate experiments, each with 9-15 WHT/Ht mice/group. Drugs were given orally in 0.1 ml 50% syrup BP for 5 days (Monday to Friday) each week, and treatment with prednisolone or mepacrine was continued until death or the end of the experiment (day 121). The doses chosen are approx...

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“…27) Therefore, the effect of indomethacin on the tumor tissues is, at least in part, due to the inhibition of the increased formation of immunosuppressing prostaglandin E 2 . We also showed that prolonged treatment with indomethacin resulted in a marked reduction of prostaglandin E 2 production in the three types of tumors.…”

Section: Discussionmentioning

confidence: 99%

Indomethacin Suppresses the Growth of Colon 26, Meth‐A and FM3A Tumors in Mice by Reducing the Prostaglandin E₂ Content and Telomerase Activity in Tumor Tissues

Ogino

Higuchi

Murata³

et al. 1999

Japanese Journal of Cancer Research

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The antitumor effect of indomethacin on Colon 26, Meth-A and FM3A tumors was investigated in mice. The prostaglandin E 2 content in tumor tissues was assayed to find out if indomethacin acts on tumors, and the telomerase activity in tumors and somatic tissues (testis, liver, spleen and colon) was also monitored during indomethacin treatment. Growth of Colon 26, Meth-A and FM3A tumors was significantly (P< < < <0.001-0.05) suppressed by indomethacin compared to the untreated controls. The prostaglandin E 2 content in the three tumors was markedly (P< < < <0.001) reduced by indomethacin. Telomerase activity in Colon 26 and FM3A tumors was significantly (P< < < <0.001) lower than that of untreated tumors (80% and 45% decrease versus the controls, respectively), and the activity in Meth-A tumor was slightly decreased (10% decrease versus the control) by indomethacin. Telomerase activity in the somatic tissues was not significantly affected by indomethacin. In summary, this study shows the effectiveness of indomethacin as an antitumor agent against three types of tumors, and suggests that indomethacin affects telomerase activity in tumors in vivo.Key words: Indomethacin -Prostaglandin E 2 -Telomerase activity -Fluorescence-based telomeric repeat amplification protocolThe antitumor effect of indomethacin on tumors in cancer patients 1, 2) and in animals 3, 4) has been described. We previously showed that indomethacin suppresses the growth of Colon 26 tumor in mice by enhancing the cellular immune function and improving cancer cachexia. 5)Indomethacin does not have a cytotoxic effect on Colon 26 tumor cells in vitro, 5) but it may have an antitumor effect via immunological pathways. We previously reported that indomethacin treatment of tumors reduces tumor size less in nude mice (deficient in T-lymphocytes) than in normal mice, compared with untreated tumors. 6)Although these results indicate that the effectiveness of indomethacin as an antitumor agent is, at least in part, due to its modification of T-cell-mediated immune functions, the precise mechanism of tumor growth suppression by indomethacin remains unknown.Recent studies have shown that many proliferating tumor cells retain a certain level of telomerase activity. [7][8][9] We previously reported that tumor growth in Colon 26-bearing mice is significantly suppressed by indomethacin treatment compared with the untreated controls, and that the telomerase activity declines preferentially in tumor tissues, while telomerase activity in somatic tissues is not significantly affected by indomethacin treatment.10) More recently, Kido et al. 11) reported that tumor size reduction by cisplatin treatment correlates with a decline in telomerase activity in tumor tissues.In this study, we transplanted Colon 26, Meth-A and FM3A tumors into normal mice to assess if the effect of indomethacin is independent of tumor cell type. Prostaglandin E 2 synthesis is inhibited by indomethacin, and therefore we measured the prostaglandin E 2 content in tumors to confirm the effect of ind...

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Treatment of mouse carcinoma in vivo with a prostaglandin E2 analogue and indomethacin

Cited by 27 publications

References 20 publications

Survival of mice with NC carcinoma is unchanged by drugs that are thought to inhibit thromboxane synthesis or increase prostacyclin formation

Survival of mice with NC carcinoma is unchanged by drugs that are thought to inhibit thromboxane synthesis or increase prostacyclin formation

Cancer in mice: effects of prednisolone or mepacrine alone and with cytotoxic drugs

Indomethacin Suppresses the Growth of Colon 26, Meth‐A and FM3A Tumors in Mice by Reducing the Prostaglandin E₂ Content and Telomerase Activity in Tumor Tissues

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Treatment of mouse carcinoma in vivo with a prostaglandin E2 analogue and indomethacin

Cited by 27 publications

References 20 publications

Survival of mice with NC carcinoma is unchanged by drugs that are thought to inhibit thromboxane synthesis or increase prostacyclin formation

Survival of mice with NC carcinoma is unchanged by drugs that are thought to inhibit thromboxane synthesis or increase prostacyclin formation

Cancer in mice: effects of prednisolone or mepacrine alone and with cytotoxic drugs

Indomethacin Suppresses the Growth of Colon 26, Meth‐A and FM3A Tumors in Mice by Reducing the Prostaglandin E2 Content and Telomerase Activity in Tumor Tissues

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Indomethacin Suppresses the Growth of Colon 26, Meth‐A and FM3A Tumors in Mice by Reducing the Prostaglandin E₂ Content and Telomerase Activity in Tumor Tissues