Adjuvant hormone therapy for localised and locally advanced prostate carcinoma: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Adjuvant hormone therapy (AHT) following radiotherapy or surgery is a treatment option frequently offered to men with localised or locally advanced prostate cancer. We performed a systematic review of published randomised trials to assess the effectiveness of AHT. METHODS: We searched MEDLINE, EMBASE, the Cochrane library, SCI, LILACS and SIGLE for randomised trials comparing AHT plus primary therapy (radiotherapy or prostatectomy) with primary therapy alone. Data on study design, participants interventions and outcomes were extracted from relevant studies and where possible pooled for meta-analysis. FINDINGS: AHT following radiotherapy improved overall survival (at 5 years OR fixed effect model 1.29, 95% CI 1.07-1.56, p=0.007), disease-specific survival (OR 2.10, 95% CI 1.53-2.88, p<0.00001) and disease-free survival (OR 1.91, 95% CI 1.16-2.23, p<0.00001). A random effect model favoured adjuvant hormone therapy but did not reach significance. After prostatectomy, there was no significant overall survival advantage with AHT, although one study reported a significant improvement in disease-specific survival (HR 4.09, p=0.0004). Disease-free survival was also better with AHT (OR 3.73, 95% CI 2.30-6.03, p<0.00001). AHT-induced toxicities included gynaecomastia, impotence, gastrointestinal and haematological. CONCLUSIONS: There are significant clinical benefits associated with the use of AHT for early prostate cancer. Patients should make an informed decision to accept AHT based on its effectiveness and side-effects.

A systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma.

BACKGROUND: We performed a systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy (NHT) in localised and locally advanced prostate cancer to assess the effectiveness of this therapy. METHODS: We searched MEDLINE, The Cochrane Library, Science Citation Index, LILACS and SIGLE for randomised trials comparing NHT plus primary therapy (radiotherapy or prostatectomy) with primary therapy alone. Data included information on study design, participants, interventions, and outcomes. Comparable data were extracted from eligible studies and pooled for meta-analysis with intention to treat principle. FINDINGS: NHT prior to prostatectomy did not improve overall or disease-free survival, but did significantly reduce positive margin rates (RR 0.49, 95% CI 0.42-0.56, p<0.00001), organ confinement (RR 1.63, 95% CI 1.37-1.95, p<0.0001) and lymph node invasion (RR 0.49, 95% CI 0.42-0.56, p<0.02). In one study NHT before radiotherapy significantly improved overall survival for men with Gleason 2-6 (p=0.015). In addition, there was a significant improvement in both clinical disease-free survival (RR 1.46, 95% CI 1.24-1.71, p<0.00001) and biochemical disease-free survival (RR 1.59, 95% CI 1.00-2.55, p=0.05). Toxicities included hot flushes, gastrointestinal, hepatic and miscellaneous adverse events. CONCLUSIONS: NHT is associated with significant clinical benefit when given with radiotherapy and improves pathological outcome prior to prostatectomy but is of minimal value prior to radical prostatectomy. The decision to use hormone therapy should be discussed between the patient, the clinician and policy maker based on the benefits, toxicity and cost.

A meta-analysis of randomised trials suggests a survival benefit for combined radiotherapy and radical cystectomy compared with radical radiotherapy for invasive bladder cancer: are these data relevant to modern practice?

OBJECTIVE: Treatment options for muscle-invasive bladder cancer include radical cystectomy or radical radiotherapy, and the prevailing choice varies by country. The ideal treatment would be a bladder-preserving therapy without compromising survival. The objective of this review was to compare the overall survival after radical surgery (cystectomy) with radical radiotherapy in patients with muscle-invasive cancer. MATERIALS AND METHODS: We searched the Cochrane Controlled Trials Register, Medline, EMBASE, Cancerlit, Healthstar and the Database of Abstracts of Reviews of Effectiveness. Authors of unpublished data were contacted. Randomised trials comparing surgery (alone or with preoperative radiotherapy) with radiotherapy were eligible for assessment. Three reviewers assessed trial quality based on the Cochrane Guidelines. Data were extracted from the text of the article or extrapolated from the Kaplan-Meier plot. The Peto odds ratio was determined to compare the overall survival and disease-specific survival. Analysis was performed on an intention-to-treat basis and treatment actually received. RESULTS: No randomised trials comparing surgery alone with radiotherapy alone were identified. Three randomised trials comparing preoperative radiotherapy followed by radical cystectomy (surgery) versus radical radiotherapy with salvage cystectomy (radical radiotherapy) were eligible for assessment. These trials represented a total of 439 patients, 221 randomised to surgery and 218 to radical radiotherapy. Three trials were combined for the overall survival results, and one was evaluable for the disease-specific survival analysis. The mean overall survival (intention-to-treat analysis) at 3 and 5 years were 45% and 36% for surgery, and 28% and 20% for radiotherapy, respectively. Peto odds ratio (95% confidence interval [CI]) analysis consistently favoured surgery in terms of overall survival. The results were significantly in favour of surgery at 3 years (OR = 1.91, 95% CI 1.30-2.82) and at 5 years (OR = 1.85, 95% CI 1.22 -2.82). On a treatment-received basis, the results were significantly in favour of surgery at 3 years (OR 1.84, 95% CI 1.17-2.90) and 5 years (OR 2.17, 95% CI 1.39-3.38) for overall survival, and at 3 years (OR 1.96, 95% CI 1.06-3.65) for disease-specific survival. CONCLUSIONS: The analysis of this review suggests that there is an overall survival benefit with combined preoperative radiotherapy plus radical surgery compared with radical radiotherapy plus salvage cystectomy in patients with muscle-invasive bladder cancer. However, it must be considered that only three trials were included for analysis, the patient numbers were small and that many patients did not receive the treatment they were randomised to. It must also be noted that many improvements in radiotherapy and surgery have taken place since the initiation of these trials; therefore, the data may not be readily extrapolated to modern practice. Ideally, a new trial comparing modern bladder-sparing therapy with the latest surgical approach to this disease is required.

Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials.

OBJECTIVE: To assess, in a systematic review and meta-analysis, the relative effectiveness of intravesical mitomycin C and bacillus Calmette-Guérin (BCG) for tumour recurrence, disease progression and overall survival in patients with medium- to high-risk Ta and T1 bladder cancer. METHODS: The major medical databases were searched comprehensively up to June 2003, and relevant journals hand-searched for randomized controlled trials, in any language, that compared intravesical mitomycin C with BCG in medium- to high-risk patients with Ta or T1 bladder cancer. RESULTS: Twenty-five articles were identified but only seven were considered eligible for the analysis. This represented 1901 evaluable patients in all, 820 randomized to mitomycin C and 1081 to BCG. Six trials had sufficient data for meta-analysis and included 1527 patients, 693 in the mitomycin and 834 in the BCG arm. There was no significant difference between mitomycin C and BCG for tumour recurrence in the six trials, with a weighted mean log hazard ratio, LHR, (variance) of -0.022 (0.005). However, there was significant heterogeneity between trials (P = 0.001). A subgroup analysis of three trials that included only high-risk Ta and T1 patients indicated no heterogeneity (P = 0.25) and a LHR for recurrence of -0.371 (0.012). With mitomycin C used as the control in the meta-analysis, a negative ratio is in favour of BCG and, in this case, was highly significant (P < 0.001). The seventh trial (in abstract form only) used BCG in low doses for two arms of the trial (27 mg and 13.5 mg) compared with a standard dose of mitomycin C (30 mg), and reported a significantly lower recurrence rate with BCG (27 mg) than for mitomycin C (P = 0.001). Only two trials included sufficient data to analyse disease progression and survival, representing 681 patients (338 randomized to BCG and 343 to mitomycin C). There was no significant difference between mitomycin C and BCG for disease progression, with a LHR of 0.044 (0.04) (P = 0.16), or survival, at -0.112 (0.03) (P = 0.50). Adverse events were slightly more frequent with BCG. Local toxicity (dysuria, cystitis, frequency and haematuria) were associated with both mitomycin C (30%) and BCG (44%). Systemic toxicity, e.g. chills, fever and malaise, occurred with both agents (12% and 19%, respectively) although skin rash was more common with mitomycin C. CONCLUSION: Tumour recurrence was significantly lower with intravesical BCG than with mitomycin C only in those patients at high risk of tumour recurrence. However, there was no difference in disease progression or survival, and the decision to use either agent might be based on adverse events and cost.

Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy--a systematic review of randomised trials.

Recent randomised studies have reported that single fraction radiotherapy is as effective as multifraction radiotherapy in relieving pain caused by bone metastasis. However, there are concerns about the higher re-treatment rates and the efficacy of preventing future complications, such as pathological fracture and spinal cord compression, by single fraction radiotherapy. A systematic review of randomised studies, examining the effectiveness of single fraction radiotherapy versus multiple fraction radiotherapy for metastatic bone pain relief and prevention of bone complications, was conducted to help answer this controversy. Randomised studies comparing single fraction radiotherapy with multifraction radiotherapy on metastatic bone pain were identified. The analyses were performed using intention-to-treat principle. The results were pooled using meta-analysis to estimate the effect of treatment on pain response, re-treatment rate, pathological fracture rate and spinal cord compression rate. Twelve trials involving 3621 sites were included in the meta-analysis. The overall pain-response rates for single fraction radiotherapy and multifraction radiotherapy were 60% (1080/1814) and 59% (1060/1807), respectively, giving an odds ratio (OR) of 1.03 (95% confidence interval [CI] 0.90-1.19), indicating no difference between the two radiotherapy schedules. There was also no difference in complete pain response rates for single fraction radiotherapy (34% [508/1476]) and multifraction radiotherapy (32% [475/1473]), with an OR of 1.10 (950% CI 0.94-1.30). Patients treated by single fraction radiotherapy had a higher re-treatment rate, with 21.5% (267/1240) requiring re-treatment compared with 7.4% (91/1236) of patients in the multifraction radiotherapy arm (OR 3.44 [95% CI 2.67-4.43]). The pathological fracture rate was also higher in single fraction radiotherapy arm patients. Three per cent (37/1240) of patients treated by single fraction radiotherapy developed pathological fracture compared with 1.6% (20/1236) for those treated by multifraction radiotherapy (OR 1.82 [95% CI 1.06-3.11]). The spinal cord compression rates were similar for both arms (OR 1.41 [95% CI 0.72-2.75]). Single fraction radiotherapy was as effective as multifraction radiotherapy in relieving metastatic bone pain. However, the re-treatment rate and pathological fracture rate were higher after single fraction radiotherapy. Studies with quality of life and health economic end points are warranted to find out the optimal treatment option.

Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer.

BACKGROUND: Tumour recurrence following transurethral resection (TUR) for Ta and T1 bladder cancer is a major clinical problem. Intravesical administration of mitomycin C (MMC) or bacillus Calmette-Guerin (BCG) has proven prophylactic activity but both are associated with local and systemic side-effects. A systematic review was carried out to compare the efficacy of these two agents. OBJECTIVES: To undertake a systematic review and meta-analysis comparing intravesical mitomycin C and Bacillus Calmette-Guerin in terms of tumour recurrence, disease progression and overall survival in Ta and T1 bladder cancer. Treatment-related toxicities would also be evaluated. SEARCH STRATEGY: A comprehensive search of MEDLINE, EMBASE, Healthstar, Cochrane Controlled Trials Register, Cancerlit, and DARE was performed, and hand searching of relevant journals undertaken. SELECTION CRITERIA: Trials in any language were included in the meta-analysis if they were properly randomised, included medium to high risk patients with Ta or T1 bladder cancer and compared intravesical MMC versus BCG. DATA COLLECTION AND ANALYSIS: Trial eligibility, methodological quality and data extraction were assessed independently by two reviewers. Time to event analysis was evaluated using log hazard ratios, with a sensitivity analysis for subgroups according to patient's risk of recurrence. MAIN RESULTS: Twenty-five articles were identified but only seven were considered eligible. This represented 1901 evaluable patients in total, 820 randomised to MMC and 1081 to BCG. Six trials had sufficient data for meta-analysis and included 1527 patients, 693 in the mitomycin arm and 834 in the BCG arm. The weighted mean log hazard ratio (variance) for tumour recurrence for the six trials was - 0.022 (0.005). This indicated no significant difference between MMC and BCG (p = 0.76). However, the meta-analysis indicated evidence of significant heterogeneity between trials (p = 0.001). A subgroup analysis of three trials that included only high risk Ta and T1 patients indicated no heterogeneity (p = 0.25) and a log hazard ratio (variance) for recurrence of -0.371 ( 0.012). With MMC used as the control in the meta-analysis, a negative ratio is in favour of BCG and, in this case, is highly significant (p = 0.0008). The seventh trial, in abstract form only, used BCG in low doses for two arms of the trial (27 mg and 13.5mg) compared to a standard dose of mitomycin C (30mg), and reported a significantly reduced recurrent rate with BCG (27mg) compared to mitomycin C (p = 0.001). Only two trials included sufficient data to analyse disease progression and survival, representing a total of 681 patients; 338 randomised to BCG and 343 to MMC. There was no significant difference between MMC and BCG for disease progression (log hazard ratio + variance: 0.044 + 0.04, p = 0.16) or survival (-0.112 + 0.03, p = 0.50). Local toxicities (dysuria, cystitis, frequency, and haematuria) were associated with both MMC (30%) and BCG (44%). Systemic toxicities, such as chills, fever and malaise, were observed with both MMC and BCG (12% and 19%, respectively) although skin rash was more common with MMC. REVIEWER'S CONCLUSIONS: The data from the present meta-analysis indicate that tumour recurrence was significantly reduced with intravesical BCG compared to MMC only in the subgroup of patients at high risk of tumour recurrence. However, there was no difference in terms of disease progression or survival, and the decision to use either agent might be based on adverse events and cost.

Treatment of testicular germ-cell cancer: a cochrane evidence-based systematic review.

Testicular germ-cell cancer is relatively rare, affecting less than 6 men per 100,000 in the UK, nevertheless, it is the most common cancer in men under 45 years. The two main types of tumours, seminomas and non-seminomas, respond to treatment differently. The standard treatment for stage I seminomas following orchidectomy is infradiaphragmatic lymph node irradiation with response rates approaching 100%, although surveillance is also a management option. The majority of early stage non-seminomas are cured by orchidedctomy alone. Bleomycin, etoposide and cisplatin, (BEP) is the most widely used chemotherapeutic regimen for metastatic germ cell tumours. In patients with 'good prognosis' the current focus is to reduce the drug-related toxicity but maintain the cure potential. Most attempts using dose reduction or alternative regimens have not proved superior to BEP. In patients with 'poor prognosis' the aim has been to increase the efficacy of treatment using high-dose chemotherapy and investigate new regimens. This article comprehensively reviews the treatment of testicular germ cell cancer with emphasis on high-grade evidence from randomised controlled trials.

Surgery versus radiotherapy for muscle invasive bladder cancer.

BACKGROUND: Muscle invasive bladder cancer is a serious clinical problem and is fatal for the majority of patients. Alternative treatments for this condition are radical cystectomy or radical radiotherapy. The choice of treatment varies according to the resident country. The ideal treatment would be a bladder preserving therapy with total eradication of the tumour without compromising survival. OBJECTIVES: The objective of this review was to compare the overall survival after radical surgery (cystectomy) versus radical radiotherapy in patients with muscle invasive cancer. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (July 2001), MEDLINE (July 2001), EMBASE (July 2001), CancerLIT (July 2001), Healthstar (July 2001) and the Database of Abstracts of Reviews of Effectiveness (July 2001). Attempts to contact authors of unpublished data were undertaken. SELECTION CRITERIA: Randomised trials comparing surgery versus radiotherapy were eligible for assessment. DATA COLLECTION AND ANALYSIS: Three reviewers assessed trial quality based on the Cochrane Guidelines. Data were extracted from the text of the article or extrapolated from the Kaplan-Meier plot. The Peto odds ratio was determined to compare the overall survival and disease-specific survival. Analysis was performed on an intention-to-treat basis and treatment actually received. MAIN RESULTS: Three randomised trials comparing pre-operative radiotherapy followed by radical cystectomy (surgery) versus radical radiotherapy with salvage cystectomy (radical radiotherapy) were eligible for assessment. These trials represented a total of 439 patients, 221 randomised to surgery and 218 to radical radiotherapy. Three trials were combined for the overall survival results and one for the disease-specific analysis [Bloom 1982]. The mean overall survival (intention-to-treat analysis) at 3 and 5 years were 45% and 36% for surgery, and 28% and 20% for radiotherapy, respectively. Peto odds ratio (95% Confidence Interval) analysis consistently favoured surgery in terms of overall survival. The results were significantly in favour of surgery at 3 years (OR = 1.91, 95% CI 1.30 -2.82) and at 5 years (OR = 1.85 95% CI 1.22 - 2.82). On a 'treatment received' basis, the results were significantly in favour of surgery at 3 (OR = 1.84, 95% CI 1.17 - 2.90) and 5 years (OR = 2.17, 95% CI 1.39 - 3.38) for overall survival and at 3 years (OR = 1.96, 95% CI 1.06,3.65) for disease-specific survival. REVIEWER'S CONCLUSIONS: The analysis of this review suggests that there is an overall survival benefit with radical surgery compared to radical radiotherapy in patients with muscle-invasive bladder cancer. However, it must be considered that only three trials were included for analysis, the patients numbers were small and that many patients did not receive the treatment they were randomised to. It must also be noted that many improvements in both radiotherapy and surgery have taken place since the initiation of these trials.

Surgery versus radiotherapy for muscle invasive bladder cancer.

BACKGROUND: Muscle invasive bladder cancer is a serious clinical problem and is fatal for the majority of patients. Alternative treatments for this condition are radical cystectomy or radical radiotherapy. The choice of treatment varies according to the resident country. The ideal treatment would be a bladder preserving therapy with total eradication of the tumour without compromising survival. OBJECTIVES: The objective of this review was to compare the survival after radical surgery (cystectomy) versus radical radiotherapy in patients with muscle invasive cancer. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (July 2000), Medline (July 2000), EMBASE (July 2000), Cancerlit (July 2000), Healthstar (July 2000) and the Database of Abstracts of Reviews of Effectiveness (July 2000). Attempts to contact authors of unpublished data were undertaken. SELECTION CRITERIA: Randomised trials comparing surgery versus radiotherapy were eligible for assessment. DATA COLLECTION AND ANALYSIS: Three reviewers assessed trial quality based on the Cochrane Guidelines. Data was extracted from the text of the article or extrapolated from the Kaplan-Meier plot. The Peto odds ratio was determined to compare the overall-survival and disease-specific survival. Analysis was performed on an intention-to-treat basis and treatment actually received. MAIN RESULTS: Three randomised trials comparing pre-operative radiotherapy followed by radical cystectomy (surgery) versus radical radiotherapy with salvage cystectomy (radical radiotherapy) were eligible for assessment. These trials represented a total of 439 patients, 221 randomised to surgery and 218 to radical radiotherapy. Peto odds ratio analysis consistently favoured surgery in terms of survival. It was significant at 3 (OR = 2.11, 95% CI 1.10,4.07) and 5 years (OR = 2.40, 95% CI 1.35, 4.29) for overall survival and at 3 years (OR = 1.96, 95% CI 1.06,3.65) for disease-specific survival for patients that actually received the protocol treatment. On an intention-to-treat analysis for disease-specific survival, the results were significantly in favour of surgery at 3 years (OR = 1.96, 95% CI 1.06,3.65) but not at 5 years. REVIEWER'S CONCLUSIONS: The evidence from this review suggests that there is no overall statistically significant benefit to radiotherapy or surgery ( with pre-operative radiotherapy) in muscle invasive bladder cancer in terms of survival, but the trends consistently favour surgery.

A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer.

OBJECTIVE: To assess, in a systematic review, the effectiveness of intravesical bacillus Calmette-Guérin (BCG) in preventing tumour recurrence in patients with medium/high risk Ta and T1 bladder cancer. PATIENTS AND METHODS: An electronic database search of Medline, Embase, DARE, the Cochrane Library, Cancerlit, Healthstar and BIDS was undertaken, plus hand searching of the Proceedings of ASCO, for randomized controlled trials, in any language, comparing transurethral resection (TUR) alone with TUR followed by intravesical BCG in patients with Ta and T1 bladder cancer. RESULTS: The search identified 26 publications comparing TUR with TUR + BCG. Six trials were considered acceptable, representing 585 eligible patients, 281 in the TUR-alone group and 304 in the TUR + BCG group. The major clinical outcome chosen was tumour recurrence. The weighted mean log hazard ratio for the first recurrence, taken across all six trials, was -0.83 (95% confidence interval -0.57 to -1.08, P < 0.001), which is equivalent to a 56% reduction in the hazard, attributable to BCG. The Peto odds ratio for patients recurring at 12 months was 0.3 (95% confidence interval of 0.21-0.43, P < 0.001), significantly favouring BCG therapy. Manageable toxicities associated with intravesical BCG were cystitis (67%), haematuria (23%), fever (25%) and urinary frequency (71%). No BCG-induced deaths were reported. CONCLUSION: TUR with intravesical BCG provides a significantly better prophylaxis of tumour recurrence in Ta and T1 bladder cancer than TUR alone. Randomized trials are still needed to address the issues of BCG strain, dose and schedule, and to better quantify the effect on progression to invasive disease.

Intravesical Bacillus Calmette-Guerin in Ta and T1 Bladder Cancer.

BACKGROUND: Intravesical therapy with Bacillus Calmette-Guerin (BCG) aims to reduce the incidence of tumour recurrence following transurethral resection (TUR) for patients with superficial bladder cancer. OBJECTIVES: The objective of this review was to compare the incidence of tumour recurrence after the standard therapy of transurethral resection versus transurethral resection plus intravesical Bacillus Calmette-Guerin. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (March 2000), Medline (February, 2000), EMBASE (February, 2000), Cancerlit (February, 2000), Healthstar (February, 2000), Database of Abstracts of Reviews of Effectiveness (February, 2000) and the Bath Information Data Service. The Proceedings of the American Society Clinical Oncology was hand searched (1996 - 1999). SELECTION CRITERIA: Randomised or quasi-randomised trials of transurethral resection alone versus transurethral resection plus intravesical Bacillus Calmette-Guerin. Patients with Ta and T1 bladder cancer of medium or high risk of tumour recurrence, were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Four reviewers assessed trial quality and two abstracted the data independently. The Peto odds ratios and log hazard ratios were determined to compare the number of patients with disease recurrence at 12 months and the rate of recurrence, respectively. MAIN RESULTS: Six randomised trials were included involving 585 eligible patients. There were significantly fewer patients with disease recurrence at 12 months in the BCG plus TUR group compared to those that received TUR alone (odds ratio 0.30, CI 0.21, 0.43). The overall log hazard ratio for recurrence (-0.83, variance 0.02) indicated a significant benefit of BCG treatment in reducing tumour recurrence. Toxicities associated with BCG consisted mainly of cystitis (67%), haematuria (23%), fever (25%) and urinary frequency (71%). No BCG-induced deaths were reported. REVIEWER'S CONCLUSIONS: In patients with medium/high risk Ta or T1 bladder cancer, immunotherapy with intravesical BCG following TUR appears to provide a significant advantage over TUR alone in delaying tumour recurrence.

Structure-activity studies on gossypol in tumor cell lines.

Gossypol [(2,2'-binaphthalene)-8,8'-dicarboxaldehyde-1,1',6,6',7,7'-hexahydroxy-5,5'-diisopropyl-3,3'-dimethyl] 1a is a naturally occurring compound extracted from the cotton plant and has been extensively studied as an oral male contraceptive. Its favorable toxicity profile, and the more recent demonstration of anti-tumor activity in animals and humans, prompted us to investigate the role of the aldehyde groups in a structure-activity study in cultured tumor cells. Four racemic compounds were evaluated: gossypol 1a, gossypolone 2, the bis Schiff's base of L-phenylalanine methyl ester with gossypol (bis Schiff's base) 1c and apogossypol 1b. The former two compounds both retain the aldehyde functional groups at positions 8 and 8' of the molecule whilst in the latter two compounds the aldehydes are blocked or absent, respectively. In addition, the l- and d-isomers of gossypol 1a, the bis Schiff's base 1c and the half Schiff's base 1d (one aldehyde blocked) were tested. The cell lines studied included melanoma (SK-mel-19), cervix (Sihas), small cell lung (H69) and myelogenous leukemia (K562). Cytotoxicity was measured using the MTT and flow cytometric viability assays. Racemic gossypol 1a and gossypolone 2 induced similar dose-dependent decreases in cell viability in all the cell lines with IC50 values of 23-46 and 28-50 microM, respectively. In contrast, the racemic bis Schiff's base derivative of gossypol 1c and apogossypol 1b showed minimal activity in any cell line up to 50 microM. The l-enantiomer of gossypol 1a was significantly more active than the d-enantiomer (IC50 of 20 versus > 50 microM, respectively). When one aldehyde of either enantiomer was blocked 1d cytoxicity was comparable to the l-enantiomer of gossypol. The data suggest that only one aldehyde group is required for the cytotoxicity of gossypol 1a, irrespective of the stereoconfiguration.

Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines.

The naturally occurring compound, gossypol, has been previously used as a male oral contraceptive, for the treatment of benign gynaecological conditions and cancer patients. Long-term daily dosing with gossypol is associated with minimal side effects and no myelosuppression. Since gossypol exhibits atropisomerism due to the restricted rotation about the 2,2' carbon bond, we have isolated the l- and d-isomers by Schiff's base formation using a chiral amine and regenerated the enantiomers by acid hydrolysis. The enantiomers and the proposed oxidative metabolite, gossypolone, were characterized by HPLC, 1H-NMR and optical rotation. The cytotoxicity was assessed in cell cultures derived from melanoma, lung, breast, cervix, and leukaemia using the MTT viability assay. The cytotoxicity of gossypolone was similar to racemic gossypol in five out of the six cell lines studied. The l-enantiomer of gossypol induced a dose-dependent cell kill in all cell lines with a mean IC50 of 20 microM and was significantly more potent than racemic gossypol, the d-enantiomer of gossypol and gossypolone. In addition, when the leukaemia line was exposed to l-gossypol (0.5-10 microM) over a 4-day period, a schedule-dependent decrease in cell viability was observed. l-Gossypol was also compared with respective drugs used to treat patients with melanoma, lung cancer and leukaemia. The data indicate that l-gossypol was significantly more active than cisplatin, melphalan and dacarbazine in the two melanoma lines, cisplatin and daunorubicin in the lung line and hydroxyurea and busulphan in the leukaemia line. Preliminary studies using one melanoma line showed that the l-isomer induced cell shrinkage, membrane blebbing and DNA fragmentation, characteristics suggestive of apoptotic cell death.

Cytotoxicity of gossypol enantiomers and its quinone metabolite gossypolone in melanoma cell lines.

The cytotoxicity of the (-)- and (+)-isomers and the quinone metabolite gossypolone prepared from the naturally occurring polyphenolic dialdehyde gossypol were compared using two human melanoma cell lines (SK-mel-19 and SK-mel-28) with a similar growth rate, one melanotic (melanin content of 69 pg/cell) and one amelanotic (melanin content of 10 pg/cell). Results from two viability assays (MTT and flow cytometry) showed that the cytotoxicity of racemic gossypol was identical for both cell lines (50% inhibition of cell growth IC50 = 22 microM). Gossypolone at equimolar concentrations was inactive in the amelanotic cell line and as potent as racemic gossypol in the melanotic cell line. (-)-Gossypol was significantly more active in both cell lines compared with the (+)-isomer. The cytotoxic effect of (-)-gossypol was both concentration and time dependent. Under serum-free conditions, the cytotoxicity of both enantiomers was increased, suggesting that serum protein binding may play a role in the differential toxicity of these isomers in vitro. Morphological changes after exposure to (-)-gossypol included shrinkage and loss of adherence. Cell sensitivity to the (-)-isomer was five-fold greater (IC50 = 4 microM) using a clonogenic assay. At equimolar concentrations, (-)-gossypol was more cytotoxic to both cell lines than the clinically used drugs cisplatin, dacarbazine and melphalan. The results of this study suggest that (-)-gossypol may be of potential therapeutic benefit in melanoma patients.

Thermodynamic analysis of trinitrotoluene biodegradation and mineralization pathways.

Biodegradation of 2,4,6-trinitrotoluene (TNT) proceeds through several different metabolic pathways. However, the reaction steps which are considered rate-controlling have not been fully determined. Glycolysis and other biological pathways contain biochemical reactions which are acutely rate-limiting due to enzyme control. These rate-limiting steps also have large negative Gibbs free energy changes. Because xenobiotic compounds such as TNT can be used by biological systems as nitrogen, carbon, and energy sources, it is likely that their degradation pathways also contain acutely rate-limiting steps. Identification of these rate-controlling reactions will enhance and better direct genetic engineering techniques to increase specific enzyme levels.This article identifies likely rate-controlling steps (or sets of steps) in reported TNT biodegradation pathways by estimating the Gibbs free energy change for each step and for the overall pathways. The biological standard Gibbs free energy change of reaction was calculated for each pathway step using a group contribution method specifically tailored for biomolecules. The method was also applied to hypothetical "pathways" constructed to mineralize TNT using several different microorganisms. Pathways steps that have large negative Gibbs free energy changes are postulated to be potentially rate-controlling. The microorganisms which utilize degradation pathways with the largest overall (from TNT to citrate) negatiave Gibbs free energy changes were also determined. Such microorganisms can extract more energy from the starting substrate and are thus assumed to have a competitive advantage over other microorganisms. Results from this modeling-based research are consistent with much experimental work available in the literature.

A dosing scheme for carboplatin in adult cancer patients based upon pre-infusion renal function and platelet count.

The most important risk factors for the development of carboplatin-induced thrombocytopenia are total dose, glomerular filtration rate (GFR) and pre-infusion platelet count (P0). Pharmacokinetic and toxicity data from 23 patients with ovarian or testicular cancer were combined with published values from four other centers and the relationships between plasma clearance of ultrafilterable platinum and GFR, and between percentage reduction in platelet count and area under the plasma platinum curve were determined. The scatter in the data was estimated and used in a Monte-Carlo computer simulation to derive the following five-level dosing scheme. [table: see text] The scheme is based on 5% of patients incurring grade IV thrombocytopenia. Using this scheme, the majority of patients with ovarian or testicular cancer receiving carboplatin will be given an initial dose of 900 mg.

5-fluorouracil and folinic acid-induced mucositis: no effect of oral glutamine supplementation.

In some clinical situations the endogenous production of glutamine may be insufficient to maintain optimal tissue structure and function such that glutamine becomes a conditionally essential amino acid. Studies in laboratory animals have demonstrated that glutamine supplementation can reduce the incidence and severity of cytotoxic-induced mucositis. This study examined the role of oral glutamine supplementation in the management of mucositis caused by 5-fluorouracil (5-FU) and folinic acid. Twenty-eight patients with gastrointestinal cancers were randomised to receive 16 g of glutamine per day for 8 days, or placebo, in a randomised double-blind trial before crossing over to the alternative supplement during the second treatment cycle. The supplement was well tolerated with no apparent adverse effects, but failed to have any significant effect on oral mucositis assessed by the patients or investigator. The possible reasons for this apparent lack of benefit are discussed.

OC125 immunoscintigraphy in ovarian carcinoma: a comparison with alternative methods of assessment.

The membrane bound, tumour associated antigen CA125 is recognized by the monoclonal antibody OC125 and may be detected in tumour tissue and serum in over 80% of patients with epithelial ovarian carcinomas. A total of 13 immunoscintigrams using 111 MBq 131I-OC125 have been performed in 11 patients. The results have been compared with clinical examination, CT and ultrasound scans, surgical findings and serum CA125 concentrations. Macroscopic disease was present at the time of scanning in 11 patients (less than 2 cm, eight patients, greater than 2 cm, three patients). Clinical examination and ultrasound were positive in three, CT scanning in four, immunoscintography in seven and serum CA125 in eight patients. This pilot study suggest that serum CA125 estimation is the most sensitive indicator of disease activity. However, immunoscintigraphy using this agent may localize residual disease when clinical examination and other radiological investigations fail.