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PubMed1996

Treatment of Androgen-Independent Prostate Cancer.

Androgen-ablative therapy for metastatic prostate cancer is effective for 60%-80% of men, but its effects are always finite and the majority of men develop androgen-independent disease within two years. Although current therapies for androgen-independent disease have not been shown to impact on survival, recent clinical and laboratory insights offer hope for effective therapy. For instance, recent data indicate that androgen-independent disease may still be dependent on hormonal stimulation, suggesting that hormonally based therapies may provide continued benefit. Chemotherapy, especially with estramustine and etoposide, seems to be an effective combination for a majority of patients. Treatment with suramin had been hampered by its side effects, but new dosing schedules are effectively circumventing toxicity. Radioisotopes such as strontium 89 have been shown to provide effective palliation for a majority of androgen-independent patients. Overall, these and other emerging efforts may be the foundation for therapies that offer hope for a significant survival benefit.

Journal Article↗
PubMed1999

Approaches to the treatment of patients with hormone-sensitive prostate cancer.

Androgen ablation therapy provides effective palliation for patients with advanced cancer of the prostate for only a short duration because the tumor eventually develops resistance. Among the many potential molecular mechanisms involved in the development of tumor resistance to both androgen ablation therapy and chemotherapy, mutations in the p53 tumor suppressor gene, overexpression of the antiapoptotic protein bcl-2, and overexpression of the multidrug resistance protein probably play a role. Because hormone-resistant tumors demonstrate greater expression of bcl-2 and because transfection of the bcl-2 gene into hormone-sensitive tumor cells confers resistance to both hormone therapy and chemotherapy, efforts to abrogate bcl-2 in prostate tumors represent one approach to improve clinical results. Of several agents recently shown to reduce prostate-specific antigen levels in phase II studies, 13-cis-retinoic acid and interferon-alpha can reduce the expression of bcl-2 and overcome bcl-2-mediated resistance to paclitaxel in resistant cell lines. For these reasons, our current studies test the hypothesis that reducing the expression of bcl-2 with 13-cis-retinoic acid and interferon-alpha in combination with taxanes will improve clinical results. Additionally, other studies test the hypothesis that treatment early, before the development of resistance mechanisms, in hormone-sensitive disease will improve results. Studies with docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) and with estramustine combination therapy are also ongoing.

Animals↗
PubMed2000

[New combination chemotherapy in urological cancers].

Although several effective therapeutic modalities are currently available for each urological cancer, there are still many patients for whom cure is not possible. Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are both standard agents for patients with metastatic renal cell carcinoma (RCC). However, only up to 20% of patients can attain a complete response with these agents. It has been reported that for bladder transitional cell carcinoma (TCC), a cisplatin-based chemotherapy such as M-VAC chemotherapy can give patients a prognostic benefit in an adjuvant setting. There has been no therapy to improve upon M-VAC for more than a decade. In this review, several trials with new combination chemotherapies that were developed to overcome the limitations of the current therapy are discussed. These include the combination of IL-2, IFN-alpha and 5-fluorouracil for RCC, paclitaxel/gemcitabine and cisplatin/carboplatin for TCC, and paclitaxel/docetaxel and estramustine for hormone-refractory prostate cancer. The results of initial trials with these new combination therapies are promising. Large scale clinical trials, however, have yet to be done.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Regulation of Cyp1a1 induction by dioxin as a function of cell cycle phase.

Analyses of CYP1A1 mRNA were used to monitor the responsiveness of murine hepatoma 1c1c7 and human monocytic U937 cells in different phases of the cell cycle to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Concentrations of TCDD capable of inducing CYP1A1 were not cytostatic to either cell line. Steady-state CYP1A1 mRNA contents were reduced (45-90%) in TCDD-treated cultures arrested in G2/M as a consequence of exposure to microtubule disrupters (Colcemid, estramustine, vinblastine) or the microtubule stabilizer Taxol, relative to TCDD-treated asynchronous 1c1c7 cultures. The accumulation of mRNAs corresponding to Nmo1, another TCDD-inducible gene of the Ah battery, was also reduced in TCDD-treated G2/M cultures. Quantitative reverse transcriptase-polymerase chain reaction analyses of CYP1A1 heterogeneous nuclear RNA (hnRNA) revealed that Cyp1a1 transcription was suppressed in G2/M cells. This suppression reflected neither changes in the relative content of the proteins comprising the aryl hydrocarbon receptor (AHR) complex nor a suppression of AHR activation and translocation to the nucleus. Release of 1c1c7 cultures arrested in G2/M restored TCDD responsiveness. Centrifugal elutriation of TCDD-treated asynchronously growing U937 cells was used to prepare populations of cells in specific phases of the cell cycle. Within 3 h of TCDD exposure late G1/early S phase cells had CYP1A1 mRNA contents approximately 1.4- and 3-fold higher than the contents of asynchronous/early G1 and G2/M cultures, respectively. These studies suggest that the transcriptional activation of members of the Ah battery by TCDD is cell cycle-dependent, and markedly suppressed in G2/M cells.

Blotting, Western↗
PubMed2001

Mitoxantrone: new indication. More risky than beneficial in advanced prostate cancer.

(1) The reference management of advanced-stage hormone-resistant prostate cancer is palliative treatment aimed at controlling pain and improving quality of life, namely analgesics and radiotherapy for painful bone metastases. (2) Mitoxantrone, a cytotoxic agent, has been granted marketing authorisation in this indication. Estramustine was already available in this setting. (3) The clinical assessment file on mitoxantrone mainly comprises two unblinded trials comparing a steroid + mitoxantrone combination with steroid alone. Mitoxantrone has not been compared with palliative care comprising radiotherapy. (4) One trial involved 161 patients with painful metastases. They were treated either with prednisone (10 mg/day by mouth) + mitoxantrone (12 mg/m2 intravenously every 3 weeks), or with prednisone alone. The other trial involved 242 patients with metastases that were not always symptomatic, who were treated either with hydrocortisone (40 mg/day orally) + mitoxantrone (14 mg/m2 intravenously every three weeks) or with hydrocortisone alone. (5) No trial showed a benefit of mitoxantrone in terms of the duration or quality of survival. The analgesic effect of mitoxantrone in the first trial was moderate, benefiting fewer than 20% of patients. The evidence shows that radiotherapy is effective in 80% of cases. (6) The main adverse effects of mitoxantrone are haematological and cardiovascular. The adverse effect profile of mitoxantrone does not appear to be any more favourable than that of radiotherapy. (7) In practice, for patients with advanced-stage hormone-resistant prostate cancer the reference palliative treatment for painful bone metastases remains analgesics plus radiotherapy. Mitoxantrone is of no use in this setting.

Analgesics↗
PubMed2002

Docetaxel in the integrated management of prostate cancer. Current applications and future promise.

Docetaxel (Taxotere)-based regimens can be included among the most effective treatment options for the management of patients with advanced, androgen-independent prostate cancer. Results with docetaxel as a single agent and in combination regimens with estramustine (Emcyt) have consistently achieved a palliative response, reduced serum PSA levels by > or = 50%, and produced objective responses in patients with measurable disease. In addition, encouraging survival data have been demonstrated in several phase II trials. The ability to administer docetaxel on a weekly basis has substantially enhanced research efforts for treatment in prostate cancer patients. The results of ongoing phase III randomized trials evaluating docetaxel regimens in androgen-independent prostate cancer are eagerly awaited for their potential to definitively demonstrate a beneficial impact on overall patient survival. Docetaxel-containing regimens are likely to demonstrate a substantial role in the management of early-stage prostate cancer patients in the adjuvant and neoadjuvant settings, where clinical investigations are under way. In addition, study results from ongoing trials that integrate docetaxel with hormonal therapies for patients with biochemical recurrence following definitive local treatments will be important in refining the future role of chemotherapy for prostate cancer in general. The preliminary findings from studies conducted with docetaxel are encouraging and await final analysis. Finally, preliminary results from studies exploring combination regimens of docetaxel and novel agents that possess completely different mechanisms of action (eg, proapoptotic agents, angiogenesis inhibitors, and vitamin D analogs) have demonstrated the regimens to be feasible and safe, with promising early response data. These types of investigational studies will likely occupy a dominant position in future research initiatives for patients with advanced prostate cancer.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Gateways to Clinical Trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil fumarate, testosterone heptanoate, testosterone undecanoate, tipifarnib, tolterodine tartrate, topiramate, troglitazone; Ursodeoxycholic acid; Valdecoxib, valsartan, vardenafil, venlafaxine hydrochloride, VX-745.

Clinical Trials as Topic↗
PubMed2003

Microscopic pulmonary tumor embolism secondary to adenocarcinoma of the prostate.

We report a case of pulmonary tumor embolism involving multiple emboli from an unusual site, an adenocarcinoma of the prostate. A 78-year-old Japanese man was diagnosed with stage IV (1997 version of the TNM classification) moderately differentiated adenocarcinoma of the prostate in December 1997. He underwent bilateral orchiectomy and hormonal therapy with flutamide was started. The patient suffered from relapse in April 1998, and estramustine phosphate was administered as treatment for hormone-refractory prostate cancer. He noticed a dry cough in May 1998, and on June 13, he developed acute progressive dyspnea and was admitted to our hospital. Radiological findings, blood gas analysis, and clinical symptoms suggested pulmonary thrombosis. Despite anticoagulation and oxygen therapy, he remained severely dyspnoeic. He died of respiratory failure 4 days after admission. Autopsy confirmed dissemination of poorly differentiated adenocarcinoma of the prostate to the majority of the pulmonary muscular arteries.

Adenocarcinoma↗
PubMedDate not supplied

[Cell therapy and prostate cancer].

Hormonotherapy is the standard treatment for advanced prostate cancer but disease progression ineluctably occurs. Subsequent chemotherapy has a modest symptomatic palliative role even if encouraging results were recently presented with docetaxel and estramustine combination. In this context, there is a great deal of interest in using dendritic cells therapeutically, as they are the most potent professional antigen-presenting cells in the immune system. Based on their unique adjuvant capacity, two vaccinal strategies are therefore tested in clinical trials. First approach includes the administration of cancer cells transduced by a cytokine gene to stimulate the in vivo recruitment and activation of dendritic cells, and the most advanced studies use GM-CSF gene-transduced allogenic cells. The second approach consists in infusions of dendritic cells loaded ex vivo with relevant tumoral antigens. Two prostate antigens have already been used. PSMA evaluated in 130 patients and a fusion protein PAP-GM-CSF (Provenge) in 144 patients. All treatments were well tolerated and frequently generated weak specific responses, but resulted in a limited clinical efficacy. However, engineering of dendritic cells can provide optimised cell vectors able to amplify vaccine response and clinical efficacy.

Acid Phosphatase↗
PubMed2005

Recent progress in management of advanced prostate cancer.

Androgen-deprivation therapy, usually with combined androgen blockade, is standard initial treatment for advanced prostate cancer. With failure of initial treatment, as indicated by rising prostate-specific antigen (PSA) levels, second-line hormonal therapy is usually instituted. Over the past several years, it has become increasingly clear that systemic chemotherapy has an important role in hormone-refractory disease. Phase II trials have demonstrated high PSA and measurable disease response rates with taxane single-agent and combination treatments. One recent phase III trial showed that docetaxel (Taxotere)/ estramustine (Emcyt) significantly improved overall survival, progression-free survival, and PSA response rate compared with mitoxantrone (Novantrone) plus prednisone. Another phase III trial demonstrated that docetaxel given every 3 weeks plus prednisone significantly improved overall survival, PSA response rate, pain relief response rate, and quality of life compared with mitoxantrone and prednisone. On the basis of these findings, every-3-week docetaxel plus prednisone is now considered standard first-line therapy for metastatic hormone-refractory disease. There is considerable optimism that treatment can be further improved. Studies of taxane combinations with bevacizumab (Avastin), thalidomide (Thalomid), bortezomib (Velcade), antisense Bcl-2 oligonucleotide, mTOR inhibitors, epidermal growth factor receptor inhibitors, and KDR inhibitors are under way. Randomized phase III trials in progress or planned are examining docetaxel in combination with imatinib mesylate (Gleevec) or calcitriol and docetaxel/prednisone in combination with bevacizumab and an antisense clusterin compound. Other promising systemic agents include epothilones and atrasentan, and promising vaccines include Provenge, GVAX, and Prostvac.

Androgen Antagonists↗
PubMed2005

Gateways to clinical trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine.

Clinical Trials as Topic↗
PubMedDate not supplied

Palliative chemotherapy with trofosfamide in advanced prostate cancer.

BACKGROUND: A phase II study with trofosfamide in hormone-refractory prostate cancer was conducted to test the palliative efficacy. PATIENTS AND METHODS: Twenty patients suffering from advanced prostate cancer were treated with per os trofosfamide after progression on androgen ablation and/or estramustine. The mean age was 72 years. The patients were treated with 150 mg/day as continuous treatment. The treatment was continued until progressive disease or severe toxicity. RESULTS: A decline in the prostate specific antigen (PSA) level was observed in 5 patients (27%) with a 0-25% decline in 2 patients and a >50% decline in 3 patients (16%, 95% confidence interval 3.4-39.6). There were no clinical or radiological complete (CR) or partial (PR) responses in 19 evaluable patients. Some toxicity was observed: 15 patients developed anaemia and grade 2-4 adverse effects were observed in 16 patients. One patient died of cardiac event. CONCLUSION: Trofosfamide has some activity in hormone-refractory advanced prostate cancer. When used in fragile or heavily pre-treated patients, careful monitoring for haematological and cardiac effects is recommended.

Aged↗
PubMed2003

Docetaxel for the treatment of hormone-refractory prostate cancer.

Chemotherapy has historically proven toxic and ineffective for the treatment of metastatic hormone-refractory prostate cancer (HRPC), a disease with substantial morbidity and mortality. Progress has been made in symptom relief, and the combination of mitoxantrone and prednisone is considered the palliative standard of care. The effects of a variety of chemotherapeutic agents, both alone and in combination, on prostate-specific antigen decline rates, measurable disease response, and survival have been examined in numerous phase I and II trials. Results suggest that combining vinblastine or paclitaxel with estramustine confers a survival advantage over either agent alone. In addition, docetaxel-based therapy has been found to be effective and well tolerated, and phase III trials will soon determine whether docetaxel-based therapy should replace mitoxantrone-based therapy as the standard of care for HRPC.

Journal Article↗
PubMed2003

A multi-institutional pilot study of adjuvant docetaxel for patients with prostate cancer at high risk for relapse after radical prostatectomy.

The management of patients with high-risk, early-stage, prostate cancer represents a major challenge to all disciplines involved in the treatment of this common malignant neoplasm. A definition of the natural history of this disease-including the identification of key prognostic factors-and the availability of active systemic therapeutic modalities for patients with advanced disease are among the basic requirements needed to provide for early intervention in high-risk patients. Several cytotoxic chemotherapy regimens have demonstrated significant antitumor effects in patients with hormone-refractory disease. Docetaxel (Taxotere(R), Aventis Pharmaceuticals, Bridgewater, NJ), a widely used taxane with broad antitumor activity, likely represents the most active single agent in prostate cancer treatment. Current data indicate that 40%-60% of patients treated with docetaxel have exhibited evidence of benefit from treatment with docetaxel, both alone and in combination with estramustine, with acceptable toxicity. In this review we describe a pilot study that is currently entering patients at high risk for relapse after radical prostatectomy. This study was designed to evaluate the safety, feasibility, and preliminary efficacy of docetaxel given postoperatively for 6 months. The main study endpoint is time-to-biochemical-relapse, which will be assessed against a matched group of historical controls.

Journal Article↗
PubMed2003

A new paradigm for the treatment of high-risk prostate cancer: radiosensitization with docetaxel.

Survival and biochemical outcome of patients with localized, high-risk prostate cancer treated with definitive three-dimensional conformal radiation therapy (3-D CRT) with or without hormonal therapy are poor. Other therapeutic strategies are needed to improve outcome in these poor-prognostic-group patients. One such strategy involves the use of chemotherapeutic agents to radiosensitize the effects of local 3-D CRT. Very few investigators have tested this novel concept of chemotherapeutic radiosensitization. Two studies evaluated the combination of estramustine phosphate and vinblastine (EV) with radiation therapy (RT). In both studies, the combination of EV and RT resulted in moderate to severe acute and late toxicity. A recently completed, phase I trial evaluated the maximally tolerated dose (MTD) of weekly docetaxel that could be concurrently delivered with 3-D CRT (70.2 Gy) in men with high-risk prostate cancer. The MTD of concurrent weekly docetaxel with 3-D CRT was determined to be 20 mg/m(2), and this combination was shown to be safe and well tolerated. This was the first trial to evaluate taxane radiosensitization in prostate cancer. Other phase I/II studies are needed to further assess chemotherapeutic radiosensitization in localized, high-risk prostate cancer.

Journal Article↗
PubMed2003

Docetaxel for the treatment of hormone-refractory prostate cancer.

Chemotherapy has historically proven toxic and ineffective for the treatment of metastatic hormone-refractory prostate cancer (HRPC), a disease with substantial morbidity and mortality. Progress has been made in symptom relief, and the combination of mitoxantrone and prednisone is considered the palliative standard of care. The effects of a variety of chemotherapeutic agents, both alone and in combination, on prostate-specific antigen decline rates, measurable disease response, and survival have been examined in numerous phase I and II trials. Results suggest that combining vinblastine or paclitaxel with estramustine confers a survival advantage over either agent alone. In addition, docetaxel-based therapy has been found to be effective and well tolerated, and phase III trials will soon determine whether docetaxel-based therapy should replace mitoxantrone-based therapy as the standard of care for HRPC.

Journal Article↗
PubMed2003

A multi-institutional pilot study of adjuvant docetaxel for patients with prostate cancer at high risk for relapse after radical prostatectomy.

The management of patients with high-risk, early-stage, prostate cancer represents a major challenge to all disciplines involved in the treatment of this common malignant neoplasm. A definition of the natural history of this disease-including the identification of key prognostic factors-and the availability of active systemic therapeutic modalities for patients with advanced disease are among the basic requirements needed to provide for early intervention in high-risk patients. Several cytotoxic chemotherapy regimens have demonstrated significant antitumor effects in patients with hormone-refractory disease. Docetaxel (Taxotere(R), Aventis Pharmaceuticals, Bridgewater, NJ), a widely used taxane with broad antitumor activity, likely represents the most active single agent in prostate cancer treatment. Current data indicate that 40%-60% of patients treated with docetaxel have exhibited evidence of benefit from treatment with docetaxel, both alone and in combination with estramustine, with acceptable toxicity. In this review we describe a pilot study that is currently entering patients at high risk for relapse after radical prostatectomy. This study was designed to evaluate the safety, feasibility, and preliminary efficacy of docetaxel given postoperatively for 6 months. The main study endpoint is time-to-biochemical-relapse, which will be assessed against a matched group of historical controls.

Journal Article↗
PubMedDate not supplied

Some new approaches to potential test systems for drugs against prostatic cancer.

We have previously reported on test systems, based on 5alpha-reductase (5alpha-RA) and arginase activities and steroid deposition in animal prostates, potentially useful in screening drugs possibly effective in cancer of the prostate. Recently, we have concentrated on the development of other in vivo and in vitro systems which may prove of further value in testing such drugs. These systems include the following: (a) The effects of drugs on 5alpha-RA activity in human and animal non-malignant and human cancerous prostatic tissues in organ culture. The parameters necessary for the maintenance of optimal 5alpha-RA in such explants have been determined, and it has been shown that certain agents (estramustine phosphate, progesterone, estradiol-17beta) can inhibit 5alpha-RA under in vitro conditions, pointing to the potential use of such an approach in screening various cytostatic agents. In addition, 65Zn deposition, the histology, and the androgen metabolism in such tissues in organ culture are being determined as additional parameters. (b) The deposition of 65Zn in the rat dorsolateral gland, particularly as affected by prolactin and testosterone, and the effects of chemotherapeutic agents on such deposition. Methotrexate and CCNU have been shown to be potent inhibitors of 65Zn deposition in the dorsolateral gland. The parameters related to zinc metabolism in the prostate are being further investigated. (c) The demonstration of receptors for estrogens (estradiol-17beta, diethylstilbestrol) in the prostate of the baboon. The various parameters related to the specificity of such receptors have been established. The development and standardization of these approaches, some facets of which are reported in the present publication, may prove them to be more sensitive, specific, and optimal than other systems and should afford an opportunity to test various combinations of drugs potentially useful in cancer of the prostate with relative speed, efficacy, and ease of manipulation.

Adrenalectomy↗