Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats

Zaccheo, T.; Giudici, D.; Salle, E. Di

doi:10.1016/0960-0760(93)90280-a

Cited by 32 publications

(14 citation statements)

References 7 publications

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“…There was a significantly greater reduction in tumor growth with both doses of exemestane (100 and 250 g/day) used in the combined treatment than with either doses of exemestane alone or tamoxifen alone. A similar result was reported previously by Zaccheo et al, (21) who found that growth of carcinogen [7,12-dimethylbenz(a)anthracene]-induced tumors of the rat were inhibited to a greater extent by the combination of exemestane and tamoxifen than with either alone. The combined treatment, which inhibited estrogen action and estrogen synthesis, delayed tumor doubling for nearly 16 weeks, twice as long as with tamoxifen alone.…”

Section: Discussionsupporting

confidence: 78%

“…To date, it is not known whether combining a steroidal aromatase inhibitor with the antiestrogen tamoxifen will be more effective in slowing tumor progression compared with treatment with either of these drugs alone. We were particularly interested in examining the value of combining exemestane plus tamoxifen in this model as it had been reported previously that the combination is superior to either agent alone in the rat model with carcinogen [7,12-dimethylbenz(a)anthracene]-induced mammary tumors (21).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Exemestane and Tamoxifen in a Postmenopausal Breast Cancer Model

Jelovac¹,

Macedo²,

Handratta³

et al. 2004

Clinical Cancer Research

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Purpose: To optimize treatment strategies for postmenopausal breast cancer patients, we investigated the efficacy of the steroidal aromatase inhibitor exemestane alone or in combination with the antiestrogen tamoxifen in a xenograft model of postmenopausal breast cancer. We also determined the effects of these agents in sequential secondline therapy and the effect of the nonsteroidal aromatase inhibitor letrozole on tumors that progressed on the above treatments.Experimental: Aromatase-transfected human estrogen receptor-positive breast cancer cells (MCF-7Ca) were grown as tumors in ovariectomized athymic mice. Animals received subcutaneous injection with vehicle, tamoxifen, exemestane, tamoxifen plus exemestane, and letrozole. Tumor volumes were measured weekly.Results: All treatments were effective initially in suppressing tumor growth as first-line therapy compared with vehicle treatment. Exemestane suppressed tumor growth to a greater extent than tamoxifen. However, the combination of tamoxifen plus exemestane was more effective than either drug alone. After tumor volumes doubled on initial treatment, the mice were crossed over to receive exemestane or tamoxifen. Tumor growth slowed briefly in mice treated with tamoxifen and crossed over to exemestane, but tumor growth continued unabated in those changed from exemestane to tamoxifen. However, letrozole was effective in both groups as third-line therapy for a limited period. Letrozole as initial single agent was the best overall treatment in terms of the degree of tumor suppression and the length of effectiveness of treatment.Conclusion: Exemestane was more effective in controlling tumor growth than tamoxifen. In addition, the combination of exemestane plus tamoxifen was clearly more effective than sequential use of these agents in the tumor model. However, the nonsteroidal aromatase inhibitor letrozole as first-line therapy was overall the most effective treatment in controlling tumor growth.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Effects of Exemestane and Tamoxifen in a Postmenopausal Breast Cancer Model

Jelovac¹,

Macedo²,

Handratta³

et al. 2004

Clinical Cancer Research

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“…These results contrast with those of the steroidal AI exemestane and tamoxifen, wherein the combination was more effective in reducing tumor growth than either agent alone in an experimental model (Figure 3) [64,65]. A mechanism explaining the additive effects of the steroidal AI exemestane in combination with tamoxifen has not been established and warrants further evaluation.…”

Section: Combination Therapy With Selective Er Modulatorscontrasting

confidence: 47%

Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

et al. 2008

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Disclosure: W.R.M. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He has also been on the advisory board for Pfizer and received speaker's honoraria. J.B. has received honoraria and research funding from Pfizer (exemestane). A.M.H.B. has received honoraria and research support from AstraZeneca (anastrozole research). R.W.B. discloses that this article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for use in breast cancer therapy. He also received an honorarium for participating in an expert panel meeting from Pfizer/CC Ford Healthcare. E.d.S. is an employee and has stock options in Pfizer (exemestane). P.E.L. has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. A.L. discloses no conflict of interest. N.M. discloses that the article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for breast cancer treatment, and he has been on an advisory board and received honoraria from Pfizer (exemestane). T.M. has research funding from Novartis (letrozole) and has received a consulting fee from Pfizer (exemestane). H.S. has research funding and has received an honorarium from Pfizer (exemestane). P.E.G. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He also discloses that the article discusses aromatase inhibitors for prevention (Novartis, AstraZeneca, Pfizer), and that he has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. The content of this manuscript has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from any commercial bias; they have disclosed no financial relationships relevant to this content.

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“…Exemestane does not bind to steroidal receptors. In a DMBA carcinogen rat mammary cancer model, exemestane and tamoxifen combined were found to give a significantly higher response rate in established tumors than the rates for tamoxifen or exemestane alone, and the combination was more effective as a preventive intervention than either agent alone (9). In a recent limited report using an MCF-7 nude mouse model, the same group which reported absence of additive effect or synergism with anastrozole or letrozole and tamoxifen, found that exemestane and tamoxifen were additive in their tumor growth suppressant effects (10).…”

Section: Introductionmentioning

confidence: 99%

Endocrine Effects of Tamoxifen Plus Exemestane in Postmenopausal Women with Breast Cancer

Love

Hutson²,

Havighurst³

et al. 2005

Clinical Cancer Research

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Purpose: In some specific circumstances, combined hormonal therapies for breast cancer seem to be more effective than single maneuvers. In two laboratory mammary cancer models, the combination of the aromatase inactivator exemestane plus tamoxifen gives a higher response rate than is found with either agent alone.To evaluate the endocrine effects of the combination of exemestane and tamoxifen, we studied 33 postmenopausal women disease-free following primary treatments for breast cancer who were taking tamoxifen for at least 3 months.Design: After observation for symptoms on tamoxifen for 4 weeks, blood samples were taken and patients were begun additionally on exemestane 25 mg p.o. qd. Eight weeks later, blood samples were again taken, and exemestane was discontinued.Results: A decrease in alkaline phosphatase was found with exemestane treatment (P = 0.06), whereas no change in osteocalcin level was observed. A decrease in high-density lipoprotein cholesterol level was found (P = 0.0025), whereas total cholesterol, low-density lipoprotein cholesterol and triglyceride levels showed no changes with exemestane treatment. Estradiol, estrone, and estrone sulfate levels decreased to immeasurable or very low levels with exemestane treatment (all P < 0.001). No significant changes in frequencies of common drug-associated side effects, such as vasomotor symptoms or weight change, were found.Conclusions: Based on the absence of adverse endocrine effects with the addition of exemestane to tamoxifen therapy observed in this study, further clinical evaluation of the efficacy of this combination is warranted.

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Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats

Cited by 32 publications

References 7 publications

Effects of Exemestane and Tamoxifen in a Postmenopausal Breast Cancer Model

Effects of Exemestane and Tamoxifen in a Postmenopausal Breast Cancer Model

Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

Endocrine Effects of Tamoxifen Plus Exemestane in Postmenopausal Women with Breast Cancer

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