Metabolism of steroid-modifying anticancer agents

Robinson, Simon P.; Jordan, V. Craig

doi:10.1016/0163-7258(88)90112-x

Cited by 35 publications

(9 citation statements)

References 287 publications

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“…Because cytochrome P450 enzymes metabolise tamoxifen as well as other anti-estrogens (Robinson & Jordan, 1988), a high AHH activity may correlate with enzymes which inactivate the chemotherapeutic agents within the tumour itself, and may alter significantly the response of the tumour to the drug (Senler et al, 1985a). This could explain the poor prognosis of our high-AHH patients, who were treated with antiestrogens.…”

Section: Discussionmentioning

confidence: 78%

Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?

Pyykkö

Tuimala²,

Aalto³

et al. 1991

Br J Cancer

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Summary Aryl hydrocarbon hydroxylase (AHH) activity was measured in the breast tumours of 153 primary and 17 recurrent cancer patients, and in 18 patients with benign breast tumour. All operations were carried out in 1983-84. The cytosolic fraction was collected for steroid receptor determination, and microsomes were separated for AHH assay from the same tissue samples. The AHH distribution was wide and highly skewed in all groups. About 10% of the samples showed activities below detection limit. The medians and ranges for primary cancers were 34 (<5-2683), for recurrent cancers 40 (20-239) (Lynch et al., 1984;Thomas, 1984;Mettlin, 1984

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Section: Discussionmentioning

confidence: 78%

Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?

Pyykkö

Tuimala²,

Aalto³

et al. 1991

Br J Cancer

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“…The major metabolites of tamoxifen detected in patients are N-desmethyltamoxifen and 4-hydroxytamoxifen (Robinson & Jordan, 1988). The mean tumour concentrations in women on tamoxifen (40 mg daily) are 25.1 ng mg protein-1 for tamoxifen, 52 ng mg proteinfor N-desmethyltamoxifen, and 0.53 ng mg proteinfor 4-hydroxytamoxifen (Daniel et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer patients, N-desmethyltamoxifen and 4-hydroxytamoxifen are the major metabolites found in plasma and tumour cell extracts (Robinson & Jordan, 1988). Among other minor metabolites found in patient plasma, metabolite E is of note as it has been reported to be oestrogenic in rat uterus and pituitary (Murphy et al, 1987;Robinson & Jordan, 1988).…”

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confidence: 99%

Oestrogenic activity of tamoxifen and its metabolites on gene regulation and cell proliferation in MCF-7 breast cancer cells

Johnson

Westley²,

May³

1989

Br J Cancer

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Summary The effects of tamoxifen, three of its in vivo metabolites and 3-hydroxytamoxifen on cellular proliferation and the induction of four oestrogen-regulated RNAs (pNR-1, pNR-2, pNR-25 and cathepsin D) have been measured in MCF-7 breast cancer cells in phenol red-free culture medium. Tamoxifen and 3-hydroxytamoxifen acted as partial oestrogens to stimulate cell growth and the levels of the pNR-2 and pNR-25 RNAs. They were full oestrogens for the induction of cathepsin D RNA and induced the pNR-l RNA above the level found in oestrogen-treated cells. N-Desmethyltamoxifen and 4-hydroxytamoxifen behaved like tamoxifen except that N-desmethyltamoxifen did not induce the pNR-2 RNA and was only a partial oestrogen for the induction of cathepsin D RNA, and 4-hydroxytamoxifen did not induce the pNR-2 or pNR-25 RNAs. In the presence of oestradiol, the four anti-oestrogens prevented the stimulation of growth and reduced (pNR-2 and pNR-25) or increased (pNR-1) the RNA levels to those present in MCF-7 cells treated with the anti-oestrogen alone. In contrast, for cathepsin D RNA levels there was a synergistic effect of the anti-oestrogens and oestradiol. The concentration at which each anti-oestrogen was effective was related to its affinity for the oestrogen receptor. Metabolite E was a full oestrogen for the induction of cell proliferation and the oestrogen-regulated RNAs. pNR-25 and pNR-2 RNA levels correlated most closely with effects on cell proliferation. These RNAs are therefore potentially the most useful for predicting the response of breast cancer patients to tamoxifen therapy.

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“…Its clinical success has established tamoxifen as the agent of choice for endocrine therapy of breast cancer in postmenopausal women [3,4]. Recently the pharmacology [5][6][7] and metabolism [3,8] of tamoxifen has been extensively reviewed. The drug is now available to treat all stages of breast cancer.…”

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confidence: 99%

Preclinical studies with toremifene as an antitumor agent

Robinson

Parker²,

Jordan³

1990

Breast Cancer Res Tr

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Toremifene is a nonsteroidal antiestrogen currently being evaluated for the treatment of breast cancer.Toremifene (10-1°-10 -6 M) inhibited the growth of MCF-7 breast cancer cells in vitro but was ineffective against hormone-independent MDA-MB-231 cells. This activity was reproduced in vivo using the athymic mouse model. Maximal MCF-7 tumor growth was produced in athymic mice by circulating estradiol levels of approximately 200 pg/ml (from a 0.5 cm silastic capsule implanted sc). Toremifene (77 + 44/~g/day from a 2 cm silastic capsule) inhibited estradiol (0.5 cm capsule)-stimulated growth by more than 70%. No tumor growth was observed in mice treated with toremifene alone, although toremifene acted as a weak partial agonist and potent antagonist on the mouse uterus. The growth of MDA-MB-231 tumors was not influenced by either estradiol or toremifene. Toremifene (200 ~g/day) was effective in preventing the development of 7,12-dimethylbenzanthracene-induced rat mammary tumors when given po from day 28 after carcinogen administration. The antitumor activity was reversed if the toremifene was stopped. These findings indicate toremifene is a tumoristatic agent rather than a tumoricidal agent. Clinical trials with toremifene should employ an indefinite treatment strategy to control tumor recurrence in adjuvant studies.Since the first report of taxmoxifen's efficacy in 1971 [1], several hundred papers have been published describing its use in a variety of patients with breast cancer. From the review of 50 major studies, Patterson et al. reported in 1981 [2] that a third of patients are likely to obtain objective remission of their disease with tamoxifen therapy. Its clinical success has established tamoxifen as the agent of choice for endocrine therapy of breast cancer in postmenopausal women [3,4]. Recently the pharmacology [5][6][7] and metabolism [3,8] of tamoxifen has been extensively reviewed. The drug is now available to treat all stages of breast cancer.With tamoxifen as the bench mark, new antiestrogens are being sought. Some are markedly different from tamoxifen in structure (zindoxifene, ICI 164,384), while others are modifications of the tam0xifen molecule (droloxifene, toremifene) (see Fig. 1). Toremifene is being evaluated in phase I and II clinical trials [9,10], and has prompted a series of studies of this antiestrogen in different biological systems. The current status of this new antiestrogen will be reviewed.

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Metabolism of steroid-modifying anticancer agents

Cited by 35 publications

References 287 publications

Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?

Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?

Oestrogenic activity of tamoxifen and its metabolites on gene regulation and cell proliferation in MCF-7 breast cancer cells

Preclinical studies with toremifene as an antitumor agent

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