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

Stamford, I F; Melhuish, P B; Carroll, Mairéad A.; Corrigan, Christopher; Patel, Sheena; Bennett, A. B.

doi:10.1038/bjc.1986.171

Cited by 11 publications

(7 citation statements)

References 13 publications

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“…Nevertheless, our findings are weak evidence against Honn's hypothesis. They are consistent with our finding that the thromboxane synthetase inhibitor dazmegrel reduced mouse serum TXB2 and increased the 6-keto-PGF1,, but had no effect on the survival of mice bearing NC tumours (Stamford et al, 1986). Similarly, recent work in breast cancer patients demonstrated that the TXB2:6-keto-PGF1, ratio in the systemic circulation is not an indicator of malignancy or metastasis (Nigam et al, 1985).…”

Section: Discussionsupporting

confidence: 80%

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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Section: Discussionsupporting

confidence: 80%

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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“…Vasodilator, anti-aggregatory prostacyclin (PG12) and vasoconstrictor, pro-aggregatory thromboxane A2 (TxA2) are especially important in this regard, since their balance may determine, at least partly, the potential of some cancers to grow and spread. This theory has been supported by some studies (Honn & Meyer, 1981Honn et al, 1983a, but also disputed by other data (Stamford et al, 1986). That prostaglandins and prostanoids may be of significance for tumour behaviour gains support from the data that prostaglandin synthesis inhibitors increase the survival time of mice transplanted with mammary carcinoma (Bennett et al, 1982).…”

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confidence: 47%

“…It is generally thought that PGI2 or its dominance over TxA2 should prevent metastasis (Honn et al, , 1983b, but this theory has also been disputed (Stamford et al, 1986). The picture may be partly unclear due to difficulties in assessing PGI2 and TxA2 production in vivo.…”

Section: Discussionmentioning

confidence: 99%

Urinary excretion of prostacyclin and thromboxane degradation products in patients with ovarian malignancy: effect of cytostatic treatment

Aitokallio-Tallberg

Viinikka²,

Ylikorkala³

1989

Br J Cancer

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Summary We studied the effect of ovarian cancer and its chemotherapy on the urinary excretion of prostacyclin (PGI2) and thromboxane A2 (TxA2) hydration and metabolic products. In six patients we measured 6-keto-PGF,a and 2,3-dinor-6-keto-PGF,. (PGI2 products) and thromboxane B2 (TxB2) and 2,3-dinor-TxB2 (TxA2 products) by HPLC followed by radioimmunoassay before, during and after the combined infusion of cisplatin, 4'epi-adriamycin and cyclophosphamide. Before the first cytostatic infusion, the urinary excretion of prostanoids was on average 4.4-5.8 times higher than in patients with ovarian endometriosis (n= 19). The infusion of cytostatics led to a 50-120% rise in the excretion of prostanoids during the first post-infusion 9 hours, but in the subsequent 10 hours their ouput was 25-45% below the initial value and remained low for at least 2 weeks. Following repetitive courses of cytostatics (2-4 per patient), prostanoid excretion tended to normalise. These data suggest that ovarian cancer is associated with increased production of PGI2 and TxA2, and that cytostatics suppress this production. This may be of biological significance in tumour behaviour and in the effect of cytostatics.

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“…TXS has also been shown to be involved with renal cell carcinoma metastasis. Early in-vivo studies with TXS inhibitors have failed to report any beneficial effects on metastasis or spread to the lymph nodes [169]. However, when used in combination with a TP antagonist, TXS inhibitors have been found to inhibit metastasis formation from tail vein injected B16a cells, as well as spontaneous metastasis formation from subcutaneous B16a and Lewis lung carcinoma tumors [162].…”

mentioning

confidence: 99%

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

Cathcart

Reynolds

O’Byrne

et al. 2010

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described.While prostacyclin synthase is generally believed to be pro-tumor, an anti-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI 2 /TXA 2 ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase over-expression has been shown to be chemopreventative in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development.In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTProstacyclin Synthase, Thromboxane Synthase and Cancer 4 growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTProstacyclin Synthase, Thromboxane Synthase and Cancer 5 IntroductionCancer causes seven million deaths annually, accounting for 12.5% of deaths worldwide. It is the second leading cause of death in the developed world and is among the three leading causes of death for adults in developed countries. It is estimated that, by 2020there will be 16 million new cases every year, representing a 50% increase in cancer incidence [1].The arachidonic acid pathway is responsible for the generation of a wide variety of bioactive metabolites. These metabolites, otherwise known as eicosanoids, have beenshown to be involved in many different pathologies, including inflammation and cancer [2].Arachidonic acid can be metabolised into the biologically active eicosanoids via the action of three separate groups of enzymes: cyclooxygenases (COX), lipoxygenases (LOX), and epoxygenases (cyctochrome P450). The COX enzymes catalyse the first step in the synthesis of prostanoids from arachidonic acid [3]. ...

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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

Cited by 11 publications

References 13 publications

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

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

Urinary excretion of prostacyclin and thromboxane degradation products in patients with ovarian malignancy: effect of cytostatic treatment

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

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