A Phase II Study of Flutamide in Ovarian Cancer

Vassilomanolakis, M.; Koumakis, George; Barbounis, V.; Hajichristou, H; Tsousis, S; Efremidis, Anna

doi:10.1159/000227688

Cited by 25 publications

(21 citation statements)

References 12 publications

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“…Furthermore, in a nested case-control study, prediagnostic androgen levels were higher in ovarian cancer cases than in controls (4). In phase 2 clinical trials of antiandrogens as a treatment for ovarian cancer, investigators observed that antiandrogens reduced the tumor burden or stabilized the progression of ovarian cancer in some women who had previously failed at least one chemotherapy (5,6). Although data from animal models and cell lines have been less consistent (7)(8)(9), showing both stimulation and inhibition of ovarian cell growth with androgen administration, the epidemiologic and clinical data seem to suggest a role for androgens in ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

Terry¹,

Vivo

Titus-Ernstoff

et al. 2005

Cancer Research

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Biological and epidemiologic evidence suggest that androgen or its receptor may play a role in ovarian cancer pathogenesis. The most notable genetic factor influencing androgen receptor (AR) activity is the functional cytosine, adenine, guanine (CAG) repeat in which length is inversely proportional to its transactivational activity. Additional genetic variation due to single nucleotide polymorphisms in the AR gene may be captured through haplotypes. We genotyped the CAG microsatellite and six haplotype-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082) of the androgen receptor gene in 987 ovarian cancer cases and 1,034 controls from a study conducted in New Hampshire and eastern Massachusetts between May 1992 and July 2003. We estimated haplotype frequencies and calculated odds ratios with 95% confidence intervals to evaluate the association between the haplotypes and the AR CAG microsatellite with ovarian cancer risk. We observed that carriage of two alleles with z22 CAG repeats was associated with an increased risk of ovarian cancer compared with carriage of two alleles with <22 CAG repeats (covariate-adjusted odds ratios, 1.31; 95% confidence intervals, 1.01-1.69). Five common haplotypes in the AR gene were identified, but no association between these and ovarian cancer risk was observed. Our results suggest that possession of two long AR alleles (z22 CAG repeats) may be associated with increased risk of ovarian cancer compared with women with two short AR alleles (<22 CAG repeats). (Cancer Res 2005; 65(13): 5974-81)

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Section: Introductionmentioning

confidence: 99%

Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

Terry¹,

Vivo

Titus-Ernstoff

et al. 2005

Cancer Research

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“…The toxicity profile of Flutamide, unlike retinoic acids, in human studies is reportedly favorable (25). Moreover, since Flutamide works at the prostate level 11 and consequently, testosterone blood levels are not reduced, libido and potency are maintained (26).…”

Section: Discussionmentioning

confidence: 99%

Role of the TGF-B-1 in the Prevention of Prostate Cancer

Steiner¹

1999

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Public .porting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and AUTHOR(S)Mitchell Steiner, M.D. Approved for public release; distribution unlimited PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)8 ABSTRACT (Maximum 200 Words)Our preliminary data showed that antiestrogen (toremifene) and antiandrogen (flutamide) prevented cancer in the TRAMP transgenic mouse model. Moreover, retinoids have been reported to prevent prostate cancer. However, the mechanism of prostate cancer prevention by these agents is unclear. We hypothesized that these agents inhibit prostate carcinogenesis through stimulation of TGFP production. This hypothesis is being tested tested in TRAMP transgenic mice through two specific aims: 1) whether the chemopreventive biologic effects of antiandrogens, antiestrogens, and retinoic acid are mediated by TGFI31 in the TRAMP model, 2) whether prostate cancer may be prevented in the TRAMP model at the genetic level by crossbreeding with transgenic mice engineered to overexpress TGFP 1 in the prostate. By detailed wholemount and histologic analyses flutamide, and toremifene were able to delay onset of prostate cancer. The mechanism of this suppression of prostate cancer may be different for the two agents: flutamide inhibited large T antigen expression, whereas toremifene had no affect on large T antigen expression. The retinoic acid derivative did not inhibit the onset of prostate cancer and as such did not demonstrate chemopreventive activity. Transgenic mice engineered to overexpress prostatic TGF3 1 had smaller prostates. As the peptide growth factor TGFI has the ability to inhibit normal epithelial cell growth, then agents that can stimulate TGF13 2 -7 production would be expected to slow the transformation of latent prostate cancer to clinical prostate cancer. Our preliminary data showed that antiestrogen (toremifene) and antiandrogen (flutamide) prevented cancer in the TRAMP transgenic mouse 8 model. Moreover, retinoids have also been reported to prevent prostate cancer. [9][10][11][12] However, the mechanism of prostate cancer prevention by these agents is unclear. We hypothesize that these agents stimulate TGFP production that in turn inhibits prostate carcinogenesis by preventing the activation of latent prostate cancer. This hypothesis will be tested in TRAMP transgenic mice, which develop spontaneous prostate cancer with features similar to that of human prostate cancer, through two specific aims. 1) To determine whether the chemopreventive biologic effects of antian...

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“…However, it is not yet clear whether patients with lowgrade ovarian tumors do represent a group more likely to benefit from treatments affecting the GnRH axis. The AR inhibitor flutamide was assessed in two, nonrandomized phase II trials [65,66]. Tumolo and colleagues reported a response rate (RR) of 6.3% (n ϭ 2) and SD rate of 28% (n ϭ 9) with a median SD duration of 24 weeks [65].…”

Section: Clinical Trials With Compounds Affecting the Androgen Axismentioning

confidence: 99%

“…All patients were heavily pretreated (median of two chemotherapy lines) and had documented disease progression on screening. In a second trial by Vasillomanolakis and colleagues, 24 patients who progressed on chemotherapy received a low dose (100 mg three times a day) of flutamide [66]. One patient responded to the treatment (4.3%) and two patients had SD for Ն7 months.…”

Section: Clinical Trials With Compounds Affecting the Androgen Axismentioning

confidence: 99%

Revisiting the Role of Antiandrogen Strategies in Ovarian Cancer

et al. 2011

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After completing this course, the reader will be able to:1. Explain the role of the androgen axis in the development of ovarian cancer.2. Discuss the potential compounds with anti-androgen activity that can be assessed for the treatment of patients with ovarian cancer.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTAndrogen receptors are frequently expressed in epithelial ovarian cancer (EOC). Their role in the development of EOC is not fully understood. In the present review we first discuss the epidemiological data linking a hyperandrogen state to a higher risk for ovarian cancer, second describe in vitro studies of the role of androgens in influencing the growth of EOC, and finally review the completed clinical trials with compounds that exploit the androgen axis in patients with ovarian cancer. The therapeutic approaches that inhibit androgen signaling have so far produced only modest response rates. In the light of new data regarding the role of androgen stimulation in the evolution of EOC and the emergence of new compounds used for the treatment of other hormone-driven malignancies, such as prostate and breast cancer, we provide suggestions for new studies of antiandrogen therapeutics in the treatment of EOC. A specific example is the new agent abiraterone. In addition, we propose a panel of molecules that could be assessed as potential biomarkers that may aid patient selection for this approach in the future. The Oncologist

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A Phase II Study of Flutamide in Ovarian Cancer

Cited by 25 publications

References 12 publications

Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

Role of the TGF-B-1 in the Prevention of Prostate Cancer

Revisiting the Role of Antiandrogen Strategies in Ovarian Cancer

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