UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bicalutamide (Casodex) has been approved as a new option for the treatment of prostate cancer. It is a new non-steroidal anti-androgen synthesized by the British company Zeneca. In pharmacological studies using rats and other subjects, the product showed excellent affinity with androgen receptors and was found to be anti-androgen active and effective against tumors, and so clinical trials have begun. Approval has been obtained in approximately 70 countries, including the United Kingdom, the United States and Germany. Anti-androgens are used extensively in combination with LHRH analogs or surgical castration (MAB therapy) in the treatment of prostate cancer. Overseas, encouraging results have been obtained from comparative trials using bicalutamide or flutamide in MAB therapy. Bicalutamide is expected to be highly effective. Moreover, it can be administered in a once-daily dose, which is expected to improve patient compliance. In a late Phase II study in Japan, a response rate as high as 64.4% was achieved when bicalutamide was administered alone. The potential for bicalutamide to be used alone is important because of the growing emphasis on patient quality of life and sexual function in prostate cancer therapy.
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PMID:[A new anti-androgen, bicalutamide (Casodex), for the treatment of prostate cancer--basic clinical aspects]. 1043 91

Our earlier report suggested that androst-5-ene-3beta,7beta-diol (Delta(5)-androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyflutamide (Eulexin) and bicalutamide (Casodex), fail to block completely the Adiol-induced androgen receptor (AR) transactivation in prostate cancer cells. Here, we report the development of a reporter assay to screen several selective steroids with anti-Adiol activity. Among 22 derivatives/metabolites of dehydroepiandrosterone, we found 4 steroids [no. 4, 1,3,5(10)-estratriene-17alpha-ethynyl-3, 17beta-diol; no. 6, 17alpha-ethynyl-androstene-diol; no. 8, 3beta, 17beta-dihydroxy-androst-5-ene-16-one; and no. 10, 3beta-methylcarbonate-androst-5-ene-7,17-dione] that have no androgenic activity and could also block the Adiol-induced AR transactivation in prostate cancer PC-3 cells. Interestingly, these compounds, in combination with hydroxyflutamide, further suppressed the Adiol-induced AR transactivation. Reporter assays further showed that these four anti-Adiol steroids have relatively lower glucocorticoid, progesterone, and estrogenic activity. Together, these data suggest some selective steroids might have anti-Adiol activity, which may have potential clinical application in the battle against the androgen-dependent prostate cancer growth.
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PMID:Suppression of Delta(5)-androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells. 1050 Jan 49

Prostate cancer, acne, seborrhea, hirsutism, and androgenic alopecia are well recognized to depend upon an excess or increased sensitivity to androgens or to be at least sensitive to androgens. It thus seems logical to use antiandrogens as therapeutic agents to prevent androgens from binding to the androgen receptor. The two predominant naturally occurring androgens are testosterone (T) and dihydrotestosterone (DHT). DHT is the more potent androgen in vivo and in vitro. All androgen-responsive genes are activated by androgen receptor (AR) bound to either T or DHT and it is believed that AR is more transcriptionally active when bound to DHT than T. The two classes of antiandrogens, presently available, are the steroidal derivatives, all of which possess mixed agonistic and antagonistic activities, and the pure non-steroidal antiandrogens of the class of flutamide and its derivatives. The intrinsic androgenic, estrogenic and glucocorticoid activities of steroidal derivatives have limited their use in the treatment of prostate cancer. The non-steroidal flutamide and its derivatives display pure antiandrogenic activity, without exerting agonistic or any other hormonal activity. Flutamide (89) and its derivatives, Casodex (108) and Anandron (114), are highly effective in the treatment of prostate cancer. The combination of flutamide and Anandron with castration has shown prolongation of life in prostate cancer. Furthermore, combined androgen blockade in association with radical prostatectomy or radiotherapy are very effective in the treatment of localized prostate cancer. Such an approach certainly raises the hope of a further improvement in prostate cancer therapy. However, all antiandrogens, developed so-far display moderate affinity for the androgen receptor, and thus moderate efficacy in vitro and in vivo. There is thus a need for next-generation antiandrogens, which could display an equal or even higher affinity for AR compared to the natural androgens, and at the same time maintain its pure antiandrogenic activity, and thus providing improved androgen blockade using possibly antiandrogens alone.
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PMID:Androgen receptor antagonists (antiandrogens): structure-activity relationships. 1063 63

We recently reported that 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits the growth of the LNCaP human prostate cancer cell line by an androgen-dependent mechanism. In the present study we examined the actions and interactions of 1,25-(OH)2D3 and the androgen 5alpha-dihydrotestosterone (DHT) on two new human prostate cancer cell lines (MDA), MDA PCa 2a and MDA PCa 2b. Scatchard analyses revealed that both cell lines express high affinity vitamin D receptors (VDRs) with a binding affinity (Kd) for [3H]1,25-(OH)2D3 of 0.1 nM. However, the MDA cell lines contain low affinity androgen receptors (ARs) with a Kd of 25 nM for [3H]DHT binding. This is 50-fold lower than the AR in LNCaP cells (Kd = 0.5 nM). Their response to DHT is greatly reduced; 2a cells do not respond to 100 nM DHT, and 2b cells show a modest response at that high concentration. 1,25-(OH)2D3 causes significant growth inhibition in both MDA cell lines, greater (for 2b cells) or lesser (for 2a cells) than that in the LNCaP cell line. Moreover, 1,25-(OH)2D3 significantly up-regulates AR messenger RNA in all three cell lines, as shown by Northern blot analysis. The growth inhibitory effect of 1,25-(OH)2D3 on LNCaP cells is blocked by the pure antiandrogen, Casodex, as we previously reported. However, Casodex (at 1 microM) did not block the antiproliferative activity of 1,25-(OH)2D3 in MDA cells. In conclusion, the growth inhibitory action of 1,25-(OH)2D3 in the MDA cell lines appears to be androgen independent, whereas the actions of 1,25-(OH)2D3 in LNCaP cells are androgen dependent. Most importantly, the MDA cell lines, derived from a bone metastasis of human prostate carcinoma, remain sensitive to 1,25-(OH)2D3, a finding relevant to the therapeutic application of vitamin D and its low calcemic analogs in the treatment of advanced prostate cancer.
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PMID:1alpha,25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms. 1087 57

Androgen ablation is standard therapy for advanced prostate carcinoma. It can be administered either as a monotherapy or as a combined androgen blockade. In the present study we have investigated molecular mechanisms which are responsible for the development of resistance to therapy in advanced prostate cancer. For this purpose, we have cultured LNCaP cells in steroid-depleted medium for 1 year. The newly generated subline LNCaP-abl was characterized. In early passages (<75) LNCaP-abl cells showed a biphasic hypersensitive response to androgenic stimulation. Passages later than 75 are inhibited by androgen. Proliferation of LNCaP-abl cells was stimulated by the pure nonsteroidal antiandrogen bicalutamide (Casodex). To improve our understanding of changes which occur during intermittent androgen ablation, we have generated the sublines LNCaP-R (reversal; cultured with fetal calf serum) and LNCaP-RA (reversal and androgen; cultured with fetal calf serum and androgen) from LNCaP-abl cells. In both cell lines an increase of the basal proliferation rate was observed. Androgen receptor expression in LNCaP-abl cells was 4-fold higher than that in parental LNCaP cells (4.7 vs. 1.2 fmol/microg protein). Androgen receptor content in LNCaP-R cells was 1.8 fmol/microg protein and in LNCaP-RA cells 1.0 fmol/microg protein. The basal androgen receptor activity was 30-fold higher in LNCaP-abl cells compared to that in parental LNCaP cells. This basal activity was reduced in LNCaP-RA cells. Both androgen and the nonsteroidal androgen receptor antagonist hydroxyflutamide induced a 2- to 4-fold higher activation of androgen receptor in LNCaP-abl than in LNCaP cells. There was a switch from an antagonist to an agonist of the nonsteroidal antiandrogen bicalutamide (Casodex) in LNCaP-abl cells. Antagonistic properties of this androgen receptor blocker were again observed in both sublines (LNCaP-R and LNCaP-RA) derived from LNCaP-abl cells. In concordance with proliferation data in vitro, growth of LNCaP-abl cells in nude mice was stimulated by bicalutamide. In contrast, supplementation of androgen led to inhibition of proliferation of these cells. The present study provides new information that is useful for a better understanding of therapy-refractory prostate cancer. It is also important for the development of new therapy strategies for advanced carcinoma of the prostate.
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PMID:Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model. 1102 27

Men with locally advanced prostate cancer face a high risk of disease progression and cancer-related death. The traditional active treatment options for locally advanced disease, either following failure of treatment of primary curative intent or newly diagnosed, are radiotherapy and castration. Radiotherapy alone has a high failure rate, although outcome can be improved by adjuvant hormonal therapy. Castration is associated with loss of libido, sexual dysfunction, osteoporosis and hot flushes, which are significant drawbacks when patients may receive treatment for several years. Monotherapy with a non-steroidal antiandrogen offers potential benefits with respect to quality of life. Studies in the adjuvant setting are in progress. In the setting of previously untreated locally advanced disease, pooled mature data (56% deaths) from two major studies indicate no significant difference in survival outcome between bicalutamide ('Casodex') 150 mg and castration. Bicalutamide 150 mg offers quality of life benefits with respect to sexual interest and physical capacity. Preliminary data suggest that bicalutamide maintains bone mineral density. Bicalutamide 150 mg is well tolerated; gynaecomastia and breast pain, common side effects of antiandrogen monotherapy, may be managed by prophylactic irradiation or surgery. Bicalutamide 150 mg monotherapy is an alternative to castration for locally advanced prostate cancer.
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PMID:Treatment of locally advanced prostate cancer--a new role for antiandrogen monotherapy? 1111 97

This article summarizes discussions of the importance of androgens and androgen antagonists in the genesis of prostate cancer. These discussions occurred at a recent symposium on prostate cancer chemoprevention sponsored by the National Cancer Institute. Considerable information exists indicating the importance of androgens in the development of prostate cancer. Trials in breast cancer indicate that estrogen antagonists prevent breast cancer-suggesting, by analogy, that the blockade of androgen action might prevent the emergence of prostate cancer. The 5alpha-reductase inhibitors block the intracellular metabolism of testosterone and inhibit the growth of the prostate. Limited data suggest that 5alpha-reductase inhibitors reduces prostate-specific antigen in men with localized and advanced, primary or recurrent prostate cancer. An ongoing national trial of 18,000 men over 50 years of age has completed accrual and will evaluate whether a standard dose of finasteride will prevent the development of prostate cancer. The toxicity profile of finasteride (Proscar, Merck & Co., West Point, PA), the only approved 5alpha-reductase inhibitor, is favorable leading to its evaluation as a potential chemopreventive agent for prostate cancer. Anti-androgens such as bicalutamide (Casodex, AstraZeneca, Wilmington, DE) are active in the treatment of prostate cancer and comparable, in some trials, to testicular androgen suppression. These data suggest that antiandrogens may be active in the prevention of prostate cancer; however, the toxicity of antiandrogens (gynecomastia, gastrointestinal toxicity) poses concerns for application in prevention studies. Opportunities for study of factors predictive or associated with the development of prostate cancer and new agents that may interrupt this process offer numerous leads that may reduce the incidence of prostate cancer.
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PMID:Androgen antagonists: Potential role in prostate cancer prevention. 1129 97

The advent of prostate-specific antigen (PSA) testing and increased patient awareness has led to patients being diagnosed with prostate cancer at an earlier stage and a younger age than previously. Adjuvant hormonal therapy to radiotherapy or prostatectomy has been shown to reduce the risk of tumour progression, and in some studies survival benefits have been demonstrated. The non-steroidal antiandrogen bicalutamide ('Casodex') has undergone extensive evaluation and is currently undergoing clinical trials as immediate therapy, either alone or as adjuvant to treatment of curative intent in patients with localized or locally advanced disease. Data from the first analysis of one of the studies in the Early Prostate Cancer (EPC) programme involving 3,603 patients have shown that, after a median follow-up of 2.6 years, the risk of prostate cancer progression was significantly reduced (by 43%) in patients receiving bicalutamide 150 mg compared with those receiving standard care alone (HR 0.57; 95% CI 0.48, 0.69; p << 0.0001). The risk of PSA progression was also significantly reduced (by 63%). At this stage the survival data are still immature. Side effects of bicalutamide were mostly gynaecomastia and breast pain, which is consistent with its pharmacology. Overall withdrawal rates were similar in the bicalutamide 150 mg and standard care alone groups. In the bicalutamide 150 mg group, withdrawals were mainly due to side effects, whereas in the group receiving standard care alone, withdrawals were mainly due to disease progression. The programme is ongoing, and survival data are awaited.
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PMID:Delaying/reducing the risk of clinical tumour progression after primary curative procedures. 1168 60

Quality of life considerations are becoming increasingly important in prostate cancer management, particularly with the trend for patients to be diagnosed at an earlier age and at an earlier stage of disease. A rising serum prostate-specific antigen (PSA) level in the absence of symptoms can cause anxiety to many patients. Patients in this situation must weigh the benefits of treatment, such as delay in time to progression and increased time without pain, against the onset of adverse events that may affect quality of life. Traditionally, the active treatment options for locally advanced disease, following either new diagnosis or failure of treatment of primary curative intent, are radiotherapy and castration (medical or surgical). Radiotherapy may affect sexuality and bowel functioning, and castration is particularly associated with loss of libido and sexual dysfunction. Studies have shown that treatment-associated side effects extending over many years are of great concern to many patients. Therefore, for treatments with similar outcomes in terms of survival or time to progression, there is good reason to consider introducing new measures of efficacy based on quality of life endpoints. Data from two large studies of bicalutamide ('Casodex') therapy in patients with locally advanced prostate cancer show that this non-steroidal antiandrogen is not only associated with comparable survival outcomes but significant health-related quality of life benefits, compared with castration. In addition, a large early prostate cancer trial has demonstrated that bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. Moreover, bicalutamide treatment was associated with fewer adverse events relating to sexual function. The risk of treatment-related side effects or influence on the total quality of life must be considered carefully for each individual patient in order to assess the most appropriate treatment option.
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PMID:Quality of life aspects of treatment options for localized and locally advanced prostate cancer. 1168 61

1,25-(OH)(2) vitamin D(3) (1,25-(OH)(2) D), the active metabolite of vitamin D, exerts antiproliferative effects on a variety of tumor cells including prostate. This inhibition requires vitamin D receptors (VDRs) as well as downstream effects on the G1 to S phase checkpoint of the cell cycle. Recent data raise the possibility that androgen plays a role in the antiproliferative effects of 1,25-(OH)(2) D in prostate cancer cells; however, this hypothesis has been difficult to test rigorously as the majority of prostate cancer cell lines (unlike human prostate tumors) lack androgen receptors (ARs). We utilized two different models of androgen-independent prostate cancer that express functional ARs and VDRs to evaluate a possible role of androgen in 1,25-(OH)(2) D mediated growth inhibition. We stably introduced the AR cDNA into the human prostate cancer cell line ALVA 31, which expresses functional VDR but is relatively resistant to growth inhibition by 1,25-(OH)(2) D. Neither ALVA-AR nor the control cells, ALVA-NEO, exhibited substantial growth inhibition by 1,25-(OH)(2) D in the presence or absence of androgen. This observation suggests that the basis for the resistance of ALVA 31 to 1,25-(OH)(2) D-mediated growth inhibition is not the lack of AR. The second model was LNCaP-104R1, an AR-expressing androgen independent prostate cancer cell line derived from androgen dependent LNCaP. 1,25-(OH)(2) D inhibited the growth of LNCaP-104R1 cells in the absence of androgen and this effect was not blocked by the antiandrogen Casodex. As was observed in the parental LNCaP cells, this effect was correlated with G1 phase cell cycle accumulation and upregulation of the cyclin dependent kinase inhibitor (CKI) p27, as well as increased association of p27 with cyclin dependent kinase 2. These findings suggest that the antiproliferative effects of 1,25-(OH)(2) D do not require androgen-activated AR but do involve 1,25-(OH)(2) D induction of CKIs required for G1 cell cycle checkpoint control.
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PMID:Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. 1185 Jan 23

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