Use of the aromatase inhibitor anastrozole in the treatment of patients with advanced prostate carcinoma.
ABSTRACT Men with prostate carcinoma initially respond to therapies designed to inhibit androgen secretion or block its action. Later, the tumors in these patients become refractory to androgen-related therapies. Therefore, additional hormonal maneuvers that would benefit these men currently are needed. Reports of androgen receptor mutations and historic clinical observations raised the hypothesis that estrogens might be involved in the proliferation of androgen-refractory prostate carcinoma.
To explore this hypothesis, 14 men with advanced prostate carcinoma that was refractory to medical or surgical orchiectomy and antiandrogens were entered into a clinical Phase II trial involving suppression of estrogens. After complete evaluation, each patient received 1 mg daily of the third-generation aromatase inhibitor anastrozole until disease progression. Follow-up included serial determinations of prostate specific antigen (PSA), measurements of evaluable lesions, and assessment of intensity of pain.
No patient experienced an objective response or disease stabilization as measured by PSA level or the greatest dimension of the lesion. Minimal improvement of bone pain was reported in two patients receiving intensive analgesic medication.
It was concluded that the dependence of androgen-insensitive prostate carcinoma on estrogens for proliferation is uncommon and that aromatase inhibitors may not have a place in the treatment of prostate carcinoma at this stage of the disease.
- SourceAvailable from: Ulrich Pfeffer[show abstract] [hide abstract]
ABSTRACT: Significant inhibition of proliferative activity in PC3 human prostate cancer cells by estradiol is reported, accompanied by experimental evidence for a specific estrogen receptor (ER). Radioligand-binding assays revealed the presence of high affinity sites of estrogen binding in the nuclear compartment of PC3 cells. In addition, using a reverse transcriptase-polymerase chain reaction system, we obtained evidence of either normal or a variant ER mRNA; the latter, which lacks the entire exon 4, is coexpressed with normal ER mRNA and has been recently characterized in our laboratories. The likelihood that the inhibitory effect exerted by estradiol could be mediated by an increase of transforming growth factor beta (TGF beta) production was also investigated. Use of monoclonal antibodies against TGF beta 1 produced a 3-fold increase of growth rate in PC3 cells; this clearly speaks for high levels of endogenous TGF beta 1. This effect was almost completely abolished after addition of 100 nM estradiol. However, we failed to demonstrate any increase of TGF beta 1 mRNA after estradiol administration using Northern blot analysis. Further studies are needed to ascertain whether the estradiol-induced growth inhibition of PC3 cells is either mediated by other TGF beta species or exerted via alternative mechanism(s).Cancer Research 04/1994; 54(5):1190-3. · 8.65 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Progression to androgen-independent growth of human prostate cancers may be mediated by alterations in the structure and/or expression of the androgen receptor (AR) gene. To date, mutations in the AR gene have largely been identified in hormone refractory tumors. In this study, single-strand conformational polymorphism analysis and DNA sequencing of the entire AR gene coding region was performed on 25 primary prostate tumors sampled prior to initiation of hormonal (i.e. , androgen ablation) therapy. Base changes leading to amino acid substitutions in the AR were identified in 11 (44%) tumors. The presence of AR amino acid substitutions was associated with decreased immunohistochemical staining for AR in tumor cells and the rapid failure of subsequent hormonal therapies. Single-strand conformational polymorphism analysis of exons 2, 3, and 8 of the X-linked hypoxanthine guanine phosphoribosyl transferase (HPRT) gene in the same samples revealed no bandshifts, suggesting that the high frequency of AR gene mutations detected was not a consequence of generalized genetic instability. These data indicate that AR gene mutations occur commonly in advanced prostate cancers prior to endocrine treatment of disease and may contribute to altered androgen responsiveness of the tumors.Clinical Cancer Research 03/1996; 2(2):277-85. · 7.84 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Cryosurgery was introduced as an alternative to radiotherapy or radical prostatectomy in the mid-1960s. Although it met the primary objective of achieving local control, it was largely abandoned due to a high incidence of complications. Technologic advances in the areas of imaging and urethral warming have renewed interest in this treatment methodology. The aim of the current study was to determine the quality of life of men enrolled in a Phase II clinical trial of cryosurgery for the treatment of localized prostate carcinoma. Men were administered the Functional Assessment of Cancer Treatment-Prostate (FACT-P) prior to their treatment and at 6 weeks and 3, 6, and 12 months posttreatment. By 12 months after cryosurgery, most of the FACT-P subscales had returned to pretreatment levels, following a decline in well-being immediately after cryosurgery. There were two exceptions to this general trend: At 12 months, impairments in social/family well-being and sexual function still remained. The average time to return to work after therapy was 3 weeks. Stay in hospital after treatment was limited to 1 day for 94% of the participants. Compared with men who received the standard treatments of radical prostatectomy and radical radiotherapy, men treated with cryosurgery appeared to have a similar quality of life, with perhaps the exception of decreased sexual function. The quality-of-life outcomes of this study support the current renewed interest in cryosurgery. The severe impairments reported in other studies were not seen in this sample. In fact, it appeared that all aspects of the participants' well-being had returned to pretreatment levels by 12 months, with the exception of sexual function.Cancer 12/1999; 86(9):1793-801. · 5.20 Impact Factor