Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer.

Nonsteroidal antiandrogens are generally used in conjunction with castration as combined androgen blockade. However, the changing profile of patients with prostate cancer has made monotherapy with a nonsteroidal antiandrogen an attractive alternative therapeutic approach, offering potential quality-of-life benefits over conventional treatment modalities. Of available antiandrogens, monotherapy with bicalutamide has been most extensively evaluated. Combined data from 2 studies at a median follow-up time of 6.3 years revealed no statistically significant difference in overall survival between bicalutamide 150-mg monotherapy and castration in patients with nonmetastatic locally advanced disease. In patients with metastatic disease, there was a statistically significant difference (6 weeks) in overall survival in favor of castration. Bicalutamide monotherapy is associated with significant quality-of-life benefits (sexual interest and physical capacity), with preliminary data suggesting that the risk of osteoporosis may also be reduced by bicalutamide 150-mg monotherapy compared with castration. In general, bicalutamide is well tolerated, with a predictable adverse-effect profile. Breast pain (40%) and gynecomastia (49%) are the most common adverse events seen during monotherapy with this drug. In summary, the availability of bicalutamide 150-mg monotherapy broadens treatment options for men with locally advanced prostate cancer, offering a viable and attractive alternative to castration in this patient population. Ongoing studies will determine the role of bicalutamide in the treatment of localized disease.

Will the experience with tamoxifen in breast cancer help define the role of antiandrogens in prostate cancer?

Breast and prostate cancers are the two predominant hormone-responsive tumours. The use of the antioestrogen tamoxifen in the treatment of breast cancer has evolved over the past 30 y from treatment for advanced breast cancer to prevention. Tamoxifen is currently the endocrine treatment of choice for advanced breast cancer and for adjuvant therapy in a broad spectrum of women whose primary tumours have functional oestrogen receptors. It has also been shown to reduce the incidence of breast cancer in high-risk women. Non-steroidal antiandrogen therapy is used in the treatment of prostate cancer, but its role is still being defined. The clinical development of tamoxifen and that of the antiandrogens are reviewed and parallels are uncovered which provide insight into contemporary and future management of hormone-responsive prostate cancer.Prostate Cancer and Prostatic Diseases (2001) 4, 72-80

Does prolonged combined androgen blockade have survival benefits over short-term combined androgen blockade therapy?

OBJECTIVES: To explore whether less than 120 days of an antiandrogen plus a luteinizing hormone-releasing hormone agonist resulted in a different survival outcome than 120 days or more of combined treatment in patients with Stage D2 prostate cancer. METHODS: Survival data were available from a previously published controlled trial that had evaluated the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with a monthly depot preparation of leuprolide or goserelin, in 813 patients with Stage D2 prostate cancer. Cox's proportional hazards regression model assessed the relative effects of the length of combined androgen blockade (CAB) therapy on survival. This analysis was repeated in the subset of patients who lived at least 2 years beyond the date of randomization. Data were obtained at a median follow-up of 160 weeks. RESULTS: A survival benefit was demonstrated for patients receiving prolonged CAB therapy, with a hazard ratio of 0.275 (95% confidence interval 0.213 to 0.355, P = 0.0001) in favor of patients who received 120 days or more of CAB therapy (median survival 1035 days versus 302 days for less than 120 days of therapy). This result was confirmed in the patients who lived at least 2 years, in whom the median survival time was increased by 35%. The hazard ratio for 120 days or more of CAB therapy versus less than 120 days was 0.415 (95% confidence interval 0.246 to 0.702, P = 0.001). CONCLUSIONS: The results of the present exploratory analysis suggest that prolonged (120 days or more) antiandrogen treatment as part of CAB therapy may result in a better survival outcome.

Exploratory analysis on the effect of race on clinical outcome in patients with advanced prostate cancer receiving bicalutamide or flutamide, each in combination with LHRH analogues. The Casodex Combination Study Group.

BACKGROUND: Black race has been associated with a significantly increased risk of prostate cancer mortality. This exploratory analysis investigated the effect of race on the clinical outcome of combined androgen blockade (CAB). METHODS: Data for analysis were obtained from a double-blind, randomized, multicenter trial comparing CAB in the form of bicalutamide (50 mg once daily) or flutamide (250 mg three times daily) plus luteinizing hormone-releasing hormone analogs (LHRHa; goserelin acetate 3.6 mg, or leuprolide acetate 7.5 mg) in 813 patients with stage D(2) prostate cancer (median follow-up, 160 weeks). Patients were analyzed according to race (African American [AA], white, or other). The primary clinical events were disease progression and survival. RESULTS: Four hundred and four patients received bicalutamide/LHRHa and 409 received flutamide/LHRHa. Although treatment with bicalutamide/LHRHa resulted in slightly longer time to progression and survival time in white and AA males than treatment with flutamide/LHRHa, the differences between the treatment groups were not statistically significant. CONCLUSIONS: No marked effect of race on clinical outcome was observed regardless of antiandrogen, suggesting that similar treatment benefits are to be expected in either race.

Bicalutamide dosages used in the treatment of prostate cancer.

BACKGROUND: Androgen deprivation is often used for the treatment of patients with prostate cancer. Androgen deprivation can be achieved by surgical castration or medical castration, with or without using an antiandrogen. Each of these treatments may be used alone, or an antiandrogen may be used alongside castration to produce combined androgen blockade therapy. METHODS: The nonsteroidal antiandrogen, bicalutamide (Casodex), has been evaluated as a component in combined androgen blockade and as monotherapy. We review the arguments that indicate why a 50-mg once-daily dose of bicalutamide is appropriate in combined androgen blockade, while ongoing clinical trials evaluate 150-mg once-daily as monotherapy in the treatment of prostate cancer. RESULTS: The choice of the 50-mg dose of bicalutamide when used in combined androgen blockade is supported by four main arguments. First, bicalutamide 50 mg is at least equivalent to, if not better than, flutamide 750 mg in terms of receptor affinity, potency, and favorable plasma concentration profile. Second, the reduction in testosterone concentrations produced by medical or surgical castration decreases the potential competition between bicalutamide and testosterone for androgen receptors in prostate cells, allowing the use of a lower dose of antiandrogen in combined androgen blockade than is necessary in monotherapy. Third, bicalutamide 50 mg has an excellent tolerability profile. Fourth, at the 50-mg dose, bicalutamide plus luteinizing hormone-releasing hormone analogue was equivalent to flutamide plus luteinizing hormone-releasing hormone analogue, although there was a trend towards longer survival with bicalutamide. Furthermore, investigations of higher doses of bicalutamide have justified evaluation of bicalutamide 150 mg as monotherapy. First, pharmacodynamic studies reveal an increasing prostate-specific antigen response with increasing dose, which appears to plateau at a dose of around 150-200 mg. Second, in an analysis with 31% mortality, bicalutamide 150 mg appeared to have equivalent efficacy compared with castration in terms of survival in patients with nonmetastatic prostate cancer. CONCLUSIONS: On the basis of available data, bicalutamide 50 mg is an appropriate dose to use in combined androgen blockade, while 150 mg is being evaluated in ongoing clinical trials as a suitable dose for monotherapy.

Comparison of goserelin and leuprolide in combined androgen blockade therapy.

OBJECTIVES: To perform exploratory analyses of data from a controlled trial that assessed the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with monthly depot preparations of leuprolide or goserelin, in patients with Stage D2 prostate cancer. One analysis compared goserelin plus antiandrogen therapy with leuprolide plus antiandrogen therapy; a second analysis compared the four combined androgen blockade (CAB) regimens. METHODS: This was a randomized, multicenter trial, open-label for luteinizing hormone releasing hormone analogue (LHRH-A) therapy, double-blind for antiandrogen therapy, with a two-by-two factorial design. Eight-hundred thirteen patients were allocated in a ratio of 2:1 to goserelin therapy (3.6 mg every 28 days) or leuprolide therapy (7.5 mg every 28 days) and 1:1 to bicalutamide therapy (50 mg once a day) or flutamide therapy (250 mg three times a day). The end points of time to progression and survival were assessed with a median of 160 weeks of follow-up. RESULTS: The percentages of progression events (70.9% versus 73.3%) and deaths (54.3% versus 56.8%) were similar for goserelin plus antiandrogen and leuprolide plus antiandrogen therapies. The hazard ratios for goserelin plus antiandrogen therapy to leuprolide plus antiandrogen therapy were 0.99 (95% confidence interval [CI] 0.84 to 1.18; P = 0.92) and 0.91 (95% CI 0.75 to 1.11; P = 0.34) for time to progression and survival, respectively. Goserelin plus antiandrogen and leuprolide plus antiandrogen therapies were generally well tolerated, and the side effects associated with depot administration occurred with a low frequency in the two groups. There were no significant differences among the goserelin plus bicalutamide, goserelin plus flutamide, or leuprolide plus bicalutamide therapy groups, but leuprolide plus flutamide therapy had a significantly poorer outcome than the other three therapies. The side-effect profiles for the four CAB groups were generally similar; diarrhea was more common among patients treated with flutamide and hematuria was more common among patients treated with bicalutamide. CONCLUSIONS: Although the results of these exploratory analyses should be interpreted with caution, they indicate that goserelin plus antiandrogen and leuprolide plus antiandrogen therapies are similarly well tolerated and have equivalent time to progression and survival, and that leuprolide plus flutamide therapy appears to be the least effective of the four CAB regimens.

Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development.

BACKGROUND: Bicalutamide (Casodex) is a new nonsteroidal antiandrogen developed for use in patients with prostate cancer. The efficacy and tolerability of bicalutamide as monotherapy and as combination therapy for patients with advanced prostate cancer have been evaluated in randomized clinical trials. Clinical trials are currently in progress to further evaluate bicalutamide as monotherapy in patients with advanced stages of disease and as adjuvant or first-line therapy in patients with early-stage disease. METHODS: A review of published trials of bicalutamide focusing on dose-ranging investigations, phase II and phase III monotherapy trials, a phase III trial of combined androgen blockade, and a safety overview. RESULTS: In dose-ranging trials, bicalutamide doses of 10-200 elicited biochemical, objective, and subjective responses; higher bicalutamide doses (up to 600 mg) have also been evaluated. A 50-mg daily dose of bicalutamide was initially evaluated as monotherapy in phase II and phase III trials; in subsequent trials, a 150-mg daily dose was investigated. A 150-mg daily dose is considered to provide equivalent survival outcome compared with castration in patients with locally advanced prostate cancer, whereas the benefits of a better quality of life and better palliation with the 150-mg daily bicalutamide dose relative to castration in patients with metastatic disease needs to be balanced against the small shortfall (median difference, 42 days) in survival. In combination with a luteinizing hormone-releasing hormone agonist analogue (LHRH-A), a 50-mg daily dose of bicalutamide has equivalent efficacy to a corresponding flutamide (250 mg three times daily) combination regimen. Treatment with the bicalutamide combination regimen resulted in a longer median survival than with the flutamide combination regimen. Bicalutamide is well tolerated when used as monotherapy or in combination with a LHRH-A. The benefits of bicalutamide as monotherapy include retention of libido and sexual potency and as combination therapy a lower incidence of diarrhea relative to flutamide. CONCLUSIONS: A 50-mg daily dose of bicalutamide is sufficient when given in combination with an agent, such as a LHRH-A, that lowers serum testosterone, but higher doses of bicalutamide may be needed when the drug is given as monotherapy. Bicalutamide, 50-mg daily, is a logical first choice for antiandrogen therapy when used in combination with an LHRH-A for the treatment of patients with advanced prostate cancer. Bicalutamide 150-mg daily is considered an effective monotherapy for use in patients with locally advanced disease. Additional clinical trials are currently in progress to further evaluate bicalutamide as a monotherapy for advanced prostate cancer and to assess its value as adjuvant or first-line therapy for early-stage prostate cancer.

Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity.

The non-steroidal antiandrogens flutamide (Eulexin((R))), nilutamide (Anandron((R))) and bicalutamide (Casodex((R))) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5alpha-DHT has higher binding affinity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an affinity two to four times higher than 2-hydroxyflutamide, the active metabolite of flutamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated that bicalutamide also exhibits greater potency in reducing seminal vesicle and ventral prostate weights and inhibiting prostate tumour growth than flutamide. Although preclinical data can give an indication of the likely clinical activity, clinical studies are required to determine effective, well-tolerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival benefits of flutamide plus a luteinising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy alone. Other studies have failed to show such survival benefits, including those comparing flutamide plus orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH-A alone. In a direct comparative study, bicalutamide (50 mg, once daily) was compared with flutamide (250 mg, three times daily), each in combination with an LHRH-A. Both therapies were well tolerated, although more patients could not tolerate flutamide therapy: 25 flutamide plus LHRH-A and 2 bicalutamide plus LHRH-A patients withdrew from therapy due to diarrhoea. There were no statistically significant differences for time to progression or survival between the two antiandrogens. This clinical trial of bicalutamide confirms the prediction from preclinical studies that a 50 mg dose of bicalutamide would be appropriate for use in patients with advanced prostate cancer, and demonstrates that this bicalutamide dose is clinically effective when administered as part of CAB.

Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group.

OBJECTIVES: To compare the efficacy and tolerability of bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with metastatic (Stage D2) prostate cancer. METHODS: This was a randomized, double-blind (for antiandrogen therapy), multicenter study with a two-by-two factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days). RESULTS: The median times to progression and death were 97 and 180 weeks for the bicalutamide plus LHRH-A group compared with 77 and 148 weeks for the flutamide plus LHRH-A group. The hazard ratio for time to progression for bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.93 (95% confidence interval [CI] 0.79 to 1.10, P = 0.41) and that for survival time was 0.87 (95% CI 0.72 to 1.05, P = 0.15). The therapies were generally well tolerated. The most common adverse event in the two groups was hot flashes. The incidence of hematuria was significantly higher for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group (12% versus 6%, P = 0.007), but no patient withdrew from therapy because of hematuria. There was a significantly (26% versus 12%, P < 0.001) higher incidence of diarrhea and more withdrawals for diarrhea (25 patients versus 2) for the flutamide plus LHRH-A group relative to the bicalutamide plus LHRH-A group. CONCLUSIONS: With a median follow-up time of 160 weeks, the combination of bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.

Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade.

PURPOSE: We determined whether decreases in prostate specific antigen (PSA) would occur after withdrawal of double-blinded antiandrogen therapy with flutamide or bicalutamide for clinical progression or increasing PSA concentration in patients receiving combined androgen blockade for advanced prostate cancer. MATERIALS AND METHODS: PSA concentrations were determined weekly for at least 6 weeks and then every other week for 6 weeks in 22 patients with stage D2 prostate cancer. All patients were withdrawn from antiandrogen therapy (8 flutamide and 14 bicalutamide) due to progression or an increasing PSA concentration. Objective response was evaluated before antiandrogen withdrawal and at week 12. RESULTS: In 4 of 8 patients (50%) withdrawn from flutamide and 4 of 14 (29%) withdrawn from bicalutamide serum PSA concentrations decreased by 50% or more. PSA responses after withdrawal of flutamide therapy occurred within the first few days, whereas those after withdrawal of bicalutamide therapy occurred within 4 to 8 weeks. Of 4 patients assessed for objective response 2 had stable disease and 2 had progression. A PSA response was observed in the 2 patients with stable disease but not the 2 with progression. CONCLUSIONS: For patients with stage D2 prostate cancer and disease progression or an increasing PSA concentration, withdrawal of antiandrogen therapy with bicalutamide or flutamide may result in a PSA response. The time to PSA response is longer with bicalutamide than with flutamide. The clinical significance of the antiandrogen withdrawal phenomenon is unknown.

The antiandrogen withdrawal syndrome in relapsed prostate cancer.

Evolving data suggest that palliation of relapsed prostate cancer can be achieved by the selective discontinuation of agents that act via steroid hormone receptors. Clinical benefit has been observed following the withdrawal of flutamide (Eulexin, Schering-Plough International), bicalutamide (Casodex, Zeneca Ltd), oestrogens, progestational agents and retinoids. For patients with progression of disease while receiving these drugs, a period of observation after withdrawal should be considered before further therapy is initiated.

Three-month depot of goserelin acetate: clinical efficacy and endocrine profile. Dutch South East Cooperative Urological Group.

OBJECTIVES: To compare the pharmacodynamics and tolerability of the new goserelin acetate 10.8-mg depot with the 3.6-mg depot in patients with advanced prostate cancer during the first 3 months of therapy. METHODS: One hundred sixty patients were randomized in two comparative studies to receive either the 10.8-mg goserelin acetate depot every 12 weeks or the 3.6-mg goserelin acetate depot every 4 weeks for 12 weeks and then the 10.8-mg depot every 12 weeks thereafter. Data for pharmacodynamic assessments were collected prospectively, whereas clinical response data were collected retrospectively. RESULTS: Serum testosterone profiles of the 10.8-mg goserelin acetate depot and the 3.6-mg goserelin acetate depot were similar; testosterone levels in both groups fell below castrate levels by day 21 after administration. Decreases in serum prostate-specific antigen level after 3 months of therapy were also similar in both groups: 94% with the 10.8-mg depot and 92.5% with the 3.6-mg depot. For all patients, the median time to progression was 152.7 weeks and the median time to death was 213.6 weeks. The safety profile of the 10.8-mg goserelin acetate depot was similar to that of the 3.6-mg depot; hot flashes was the most common adverse event. The incidence of injection site reactions was very low (2 [0.3%] of 614 administrations). CONCLUSIONS: The new 10.8-mg depot was pharmacodynamically equivalent to the current 3.6-mg depot and was well tolerated, both locally and systemically. The observed times to progression and survival were as expected in this patient population. The 10.8-mg goserelin-acetate depot provided a dosing schedule that was convenient for the patient and the physician, and it has the potential to reduce health care costs while maintaining the quality of life in patients being treated for advanced prostate cancer.

A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma. Analysis of time to progression. CASODEX Combination Study Group.

BACKGROUND: A randomized, multicenter trial, double-blind for antiandrogen therapy, compared the antiandrogens bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue therapy (LHRH-A) in 813 patients with Stage D2 prostate carcinoma. An analysis of time to progression (median follow-up, 95 weeks) was performed to augment previous analyses of time to treatment failure and time to death. METHODS: Patients were randomly assigned 1:1 to double-blind antiandrogen therapy, receiving either bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), and were assigned 2:1 to LHRH-A with goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days). The primary endpoint of the trial was time to treatment failure, defined as an adverse event leading to withdrawal of randomized therapy, objective progression, death, or withdrawal from study therapy for any reason. Secondary endpoints were time to death, quality of life, and subjective response. The current analysis of time to progression included progression data collected prospectively for 561 patients (69%) and retrospectively for 252 patients (31%). RESULTS: Disease progression occurred for 223 of 404 patients (55%) in the bicalutamide plus LHRH-A group and for 235 of 409 patients (58%) in the flutamide plus LHRH-A group. The hazard ratio for time to progression of bicalutamide plus LHRH-A to that of flutamide plus LHRH-A was 0.9 (two-sided 95% confidence interval [CI], 0.75 to 1.08; P = 0.26). The upper one-sided 95% CI was 1.05, which met the definition of equivalence (< 1.25). CONCLUSIONS: At a median follow-up time of 95 weeks, bicalutamide plus LHRH-A and flutamide plus LHRH-A had equivalent time to progression.

Worldwide activity and safety of bicalutamide: a summary review.

OBJECTIVES: To evaluate bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of bicalutamide. To evaluate bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy. RESULTS: Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule. Monotherapy trials with 50 mg of bicalutamide established its intrinsic activity, as demonstrated by subjective and objective responses and decreases in PSA concentrations. In comparison with castration, 50 mg of bicalutamide monotherapy was inferior with respect to survival. In a randomized, double-blind (for antiandrogen therapy) trial, with a median follow-up of 49 weeks, 50 mg of bicalutamide plus an LHRH-A was superior (P = 0.005) to flutamide plus an LHRH-A in delaying time-to-treatment failure and was better tolerated, as was evident from a significantly (P < 0.001) lower incidence of diarrhea and fewer withdrawals for adverse events among bicalutamide-treated patients. With longer follow-up and a 34% mortality, survival was equivalent between groups. Dose-related effects of bicalutamide on serum PSA concentrations were clearly demonstrated in the clinical trial program. With a total exposure of > 2800 patient-years, bicalutamide has been shown to be a well-tolerated therapy with a low incidence of treatment-related withdrawals. CONCLUSIONS: Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.

Defining the role of antiandrogens in the treatment of prostate cancer.

OBJECTIVES: Although antiandrogens have been used as monotherapy and in combination with other treatment modalities for management of metastatic prostate cancer, their major role to date has been one in which they are used in conjunction with surgical or medical castration for treatment of Stage D (T4/Nx/M1) carcinoma of the prostate. The widespread use of prostate-specific antigen (PSA) is increasing the number of men who are diagnosed with earlier stages of this disease, thus resulting in a greater number of definitive therapeutic procedures. Also, PSA has become the primary modality for following these patients after definitive treatment. Because the use of PSA results in the discovery of lower volume of disease and in discerning earlier recurrence of disease, the question arises as to whether an antiandrogen alone could be an adequate treatment in both neoadjuvant and adjuvant settings. METHODS: As data accumulate that point to the efficacy of combined androgen blockade in metastatic disease, a protocol has been developed to test the hypothesis of intermittent combined treatment in patients who present with minimal disease and good performance status. In this study, the antiandrogen bicalutamide will be used in combination with the luteinizing hormone-releasing hormone (LHRH) analogue goserelin acetate. Also, short-term combined androgen ablation continues to be investigated prior to both radiation therapy and radical prostatectomy for localized disease. RESULTS: Two groups of patients are ideal candidates for the use of antiandrogen monotherapy following radical prostatectomy: those whose PSA values do not fall to undetectable levels and the far larger group of men who have capsular penetration or positive surgical margins with nondetectable PSA levels. Protocols have been developed to assess the clinical potential of bicalutamide as the sole adjuvant therapy in these postprostatectomy patients, based in no small part on the relative paucity of side effects of this antiandrogen. CONCLUSIONS: Antiandrogens in general, and bicalutamide in particular, are poised to play an increasing role in the treatment of all stages of adenocarcinoma of the prostate. The safety profile of bicalutamide, combined with its long half-life, resulting in once-a-day dosing, makes it an ideal choice for clinical trials evaluating an antiandrogen, either alone or combined with reversible medical castration, in earlier stages of prostate cancer as well as in various combination regimens in metastatic disease.

[Genetic carrier detection for the Wiskott-Aldrich syndrome using restriction fragment length polymorphism analysis]. / Draagsterschaponderzoek voor het Wiskott-Aldrich-syndroom met behulp van restrictiefragmentlengte-polymorfisme-analyse.

The gene for the Wiskott-Aldrich syndrome, an X-linked immunodeficiency disease, has been mapped between the RFLP markers DXS7 and DXS14 on the short arm of the X-chromosome. Close linkage to these markers permits accurate carrier detection and prenatal diagnosis. In one family with WAS patients in two generations, RFLP analysis was applied to three women at risk. It could be determined with more than 98.5% accuracy that these women were not carriers.

Monoclonal antibodies detecting different epitopes on the Forssman glycolipid hapten.

Two hybridomas, derived by fusing mouse myeloma cells with spleen cells from a rat immunized with mouse mammary tumors, have been shown to produce antibodies that recognize cell surface antigens on mesenchymal cells in a variety of tissues. Evidence presented in this report suggests that these antibodies detect overlapping epitopes on the Forssman glycolipid hapten (GalNAc alpha 1-3GalNAc beta 1-3Gal alpha 1-4Gal beta 1-4Glc beta 1-1Cer). One antibody (33B12) reacts with the terminal sugar sequence GalNAc alpha 1-3GalNAc and is specific for Forssman. The other antibody (117C9) recognizes the internal sugar sequence GalNAc beta 1-3Gal. The terminal sugar sequence GalNAc beta 1-3Gal in globoside, as well as the internal sugar sequence GalNAc beta 1-4Gal in asialo-GM1, is not recognized as an antigenic determinant by 117C9. Nevertheless, the 117C9 antibody does not react exclusively with the Forssman antigen. In a lipid extract fractionated by Folch partition of mouse mammary tumors, the antibody also detects other glycolipids.