deslorelin and Prostatic-Neoplasms

To investigate the possibility that more complete blockade of androgens or combined androgen blockade (CAB) could lead to even longer term control of localized prostate cancer. A series of recent studies have shown important benefits on survival using medical or surgical castration in localized or locally advanced prostate cancer.. The effect of CAB on long-term control or possible cure of prostate cancer was evaluated by the absence of biochemical failure or prostate-specific antigen (PSA) rise for at least 5 years after cessation of continuous treatment. A total of 57 patients with localized or locally advanced disease received CAB for periods ranging from 1 to 11 years. Twenty patients with Stage B2/T2 prostate cancer who were treated for a median duration of 7.2 years (range 2.8 to 11.7) with CAB stopped treatment and were followed up for a median of 4.9 years. Eleven patients with Stage B2/T2 also received CAB but for only 1 year. Twenty-six patients with Stage C/T3 treated with continuous CAB for a median of 9.9 years (range 3.8 to 11.3) with undetectable PSA levels stopped treatment and were followed up for a median of 5.6 years. The median follow-up since diagnosis was 14.6 years for patients with Stage B2/T2 and 16.4 years for patients with Stage C/T3 disease.. With a minimum of 5 years of follow-up after cessation of long-term CAB, two PSA rises occurred among 20 patients with Stage T2-T3 cancer who stopped treatment after continuous CAB for more than 6.5 years, for a nonfailure rate of 90%. For the 11 patients who had received CAB for 3.5 to 6.5 years, the nonfailure rate was only 36%. The serum PSA increased within 1 year in all 11 patients with Stage B2/T2 treated with CAB for only 1 year, thus indicating that active cancer remained present after short-term androgen blockade despite undetectable PSA levels. In all patients who had biochemical failure after stopping CAB, the serum PSA level rapidly decreased again to undetectable levels when CAB was restarted and remained at such low levels afterward. Of these patients, only 1 patient had died of prostate cancer at last follow-up.. The present data suggest that long-term and continuous CAB offers the possibility of long-term control or possible cure of localized prostate cancer.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Therapy, Combination; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Longitudinal Studies; Male; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome; Triptorelin Pamoate

Docetaxel, a chemotherapeutic agent currently used for improving survival of prostate cancer patients, suffers from low therapeutic index. The objective of this study was to prepare a new docetaxel derivative conjugated to deslorelin, a luteinizing hormone-releasing hormone (LHRH) superagonist, and to determine whether it enhances docetaxel potency in vitro and in vivo. Because docetaxel is not amenable for conjugation with peptides, we introduced a -COOH group in docetaxel, forming docetaxel-hemiglutarate, and subsequently conjugated this to serine in deslorelin, forming deslorelin-docetaxel. Fourier-transform IR, (1)H-nuclear magnetic resonance, and liquid chromatography-mass spectrometry analyses confirmed deslorelin-docetaxel formation. Antiproliferative efficacy in LNCaP and PC-3 cell lines over 24, 48, and 72 hours exhibited the order deslorelin-docetaxel > docetaxel, whereas deslorelin alone had no effect, with deslorelin-docetaxel potency being 15-fold greater than docetaxel at 72 h. Further, cells pretreated with antisense oligonucleotide against LHRH receptor exhibited decreased deslorelin-docetaxel efficacy, without any change in docetaxel efficacy. Thus, deslorelin-docetaxel efficacy is likely mediated via LHRH receptor. Cell cycle analysis showed that docetaxel treatment led to arrest in G(2)-M phase, whereas deslorelin-docetaxel treatment allowed greater progression to apoptosis in both cell lines, with deslorelin-docetaxel exerting 5-fold greater apoptosis compared with docetaxel in prostate cancer cell lines. Antitumor efficacy studies in PC-3 prostate xenograft-bearing mice indicated the efficacy order deslorelin-docetaxel > docetaxel >> deslorelin > PBS, with deslorelin-docetaxel exerting approximately 5.5-fold greater tumor growth inhibition than docetaxel alone. Thus, deslorelin-docetaxel prepared in this study retains pharmacologic effects of both docetaxel and deslorelin while enhancing the antiproliferative, apoptotic, and antitumor efficacy of docetaxel by several folds in prostate cancer therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromatography, Liquid; Docetaxel; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Prostatic Neoplasms; Receptors, LHRH; Spectroscopy, Fourier Transform Infrared; Taxoids; Triptorelin Pamoate; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Clinical Trials as Topic; Endometriosis; Female; Gonadotropin-Releasing Hormone; Humans; Male; Prostatic Neoplasms; Puberty, Precocious; Triptorelin Pamoate

A case is presented of a middle-aged man suffering from stage D2 prostate cancer with pulmonary metastases who responded favorably, first, to endocrine combination therapy with the antiandrogen flutamide and an LHRH agonist for 5.5 years, and, second, to the subsequent withdrawal of Flutamide at the time of the progression of the disease. This case has several exceptional features: absence of bone metastases, pulmonary metastatic nodules characterized as focal neuroendocrine differentiation, and a positive response to antiandrogen withdrawal upon relapse of metastases after initial positive response. The concept of escape to androgen blockade and development of androgenic hypersensitivity is discussed.

Topics: Acid Phosphatase; Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Bone and Bones; Flutamide; Gonadotropin-Releasing Hormone; Humans; Lung Neoplasms; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radionuclide Imaging; Sputum; Tomography, X-Ray Computed; Triptorelin Pamoate

A series of 115 previously untreated patients displaying clinical stage C prostatic carcinoma with no evidence of distant metastases received combination therapy using the antiandrogen flutamide and the LHRH agonist [D-Trp6, des-Gly-NH(2)10]LHRH ethylamide; the average follow-up was 3.9 years. Twenty-eight patients showed treatment failure with a probability of disease-free survival of 91.2% at 2 years. Twenty patients died from prostate cancer and 10 from other causes, the survival probability being 93.4% at 2 years. Local control was achieved rapidly in all patients. Urinary obstruction and hydronephrosis were corrected in all cases. When compared with data obtained after single endocrine therapy (orchiectomy or oestrogens) or radiotherapy, the treatment failure rate at 2 years was more than 3.0-fold lower after combination therapy (8.8%) than monotherapy (28.4%). The death rate 2 years after the start of combination therapy was 6.6% and was on average 22.2% (3.6-fold higher) in the studies using monotherapy (orchiectomy or oestrogens) or radiotherapy. The present data suggest that treatment of prostate cancer with combination therapy before clinical evidence of dissemination of disease permits more efficient control of local disease and a decreased rate of progression to metastatic disease.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Carcinoma; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Prostatic Neoplasms; Survival Rate; Triptorelin Pamoate