Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinically symptomatic late injury to the rectal wall occurs in about one third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of these structures. Based on our previous observations that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall of Copenhagen rats, the authors initiated a phase I clinical trial in 1998. Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, a Karnofsky performance status of > or =70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy (20 patients) and 73.8 Gy (9 patients). Therapy was delivered using a 4-field axial technique and 3-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 minutes before irradiation on the first 15 days of therapy. Amifostine dose was escalated, in cohorts, from 500 mg to 2,500 mg. Toxicity was evaluated using the Radiation Therapy Oncology Group late morbidity scale. All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. With a median follow-up time of 21 months, 9 patients (33%) had rectal bleeding (8 grade 1, 1 grade 2). Four patients (14%) had symptoms suggestive of radiation injury, which proved to be secondary to nonrelated processes. These included preexisting nonspecific proctitis (1 patient), diverticular disease of the sigmoid colon, rectal polyp (1 patient), and ulcerative colitis (1 patient). Symptoms developed significantly more often in patients receiving 500 to 1,000 mg than in patients receiving 1,500 to 2,500 mg amifostine (7 of 14 [50%] versus 2 of 13 [15%]; P =.0325, 1-sided chi(2) test). Intrarectal application of amifostine is feasible and well tolerated. A complete lack of systemic toxicity obviates the need for close monitoring of patients during and after administration. Rectal symptomatology after external beam radiotherapy to the pelvis cannot be assumed to reflect late radiation damage, because it often is a manifestation of an unrelated pathologic process. The preliminary efficacy data are encouraging and suggest that intrarectal administration of amifostine may reduce radiation damage. Further clinical studies are warranted.
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PMID:Intrarectal application of amifostine for the prevention of radiation-induced rectal injury. 1191 90

Amifostine metabolites WR-1065 and the disulfide WR-33278 are thiol-containing polyamine analogues with potent radio- and chemoprotective properties. Some studies suggest that amifostine exerts differential cytoprotection in normal versus neoplastic tissues, but this finding remains controversial. To assess the role of the polyamine transport system in radioprotection by amifostine derivatives, human DU-145 prostate cancer cells were transfected with a cDNA that encodes antizyme (OAZ), a polyamine-inducible protein that suppresses polyamine transport under control of a minimal heat shock promoter. Selected clones expressing OAZ displayed heat shock-dependent suppression of polyamine uptake. When added to culture medium under nonreducing conditions, both WR-1065 and WR-33278 were detected as the disulfide form. Each derivative protected both parental and OAZ-transfected DU-145 cells from X-ray-induced cell killing at 37 degrees C. When cultures were heat shocked at 42 degrees C, both derivatives protected parental, but not OAZ-transfected cells from radiation-induced cell killing. Treatment of DU-145 cells with difluoromethylornithine (DFMO) suppressed intracellular putrescine and spermidine content, but increased the uptake of WR-33278-derived aminothiols. The concentration-dependent radioprotection of DU-145 cells by WR-33278 was enhanced by DFMO. Addition of exogenous putrescine reduced WR-33278-mediated radioprotection in both DFMO-treated and untreated DU-145 cells. These data demonstrate that negative regulation of the polyamine transporter, mediated by polyamines or antizyme, suppresses the uptake and radioprotective activity of amifostine derivatives. Selective exclusion of amifostine derivatives by the polyamine transporter could account for differential radio- or chemoprotection in normal versus neoplastic tissues in specific situations.
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PMID:Selective exclusion by the polyamine transporter as a mechanism for differential radioprotection of amifostine derivatives. 1200 51

Local control of carcinoma of the prostate, when treated with radiation therapy, is dose related. It is well documented that higher radiation doses can produce definitive improvement but not without an increased risk of developing gastrointestinal and/or genitourinary toxicities. Radioprotective agents, such as amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD), have been proven to reduce radiotherapy-induced toxicities to normal tissue in patients with head and neck, thoracic, and pelvic tumors. Based on this information, and in an effort to determine the effectiveness of radioprotective agents in patients with prostate cancer, our institution developed a protocol involving use of amifostine in patients with prostate cancer treated with external beam radiation to a total dose of 45 Gy and/or high-dose rate brachytherapy. High-dose rate doses are 6 Gy times three fractions for combined therapy and 9.3 Gy times four fractions for the monotherapy group. To date, 13 patients have been treated, with preliminary results indicating an acceptably low incidence of gastrointestinal and genitourinary toxicities, including no acute blood pressure changes or skin reactions. However, there have been three cases of severe cardiopulmonary events, which are discussed in detail.
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PMID:Amifostine and external beam radiation therapy and/or high-dose rate brachytherapy in the treatment of localized prostate carcinoma: preliminary results of a phase II trial. 1472 41

Tolerance of the normal rectal mucosa to radiation injury limits the dose that can be safely delivered to the prostate gland with definitive external beam radiation therapy. The radioprotective agent amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) is approved for intravenous use. Laboratory studies indicate that rectal administration results in preferential accumulation of amifostine in the rectal mucosa, and in clinical studies, neither free parent compound nor free active metabolite has been detected in the systemic circulation. This trial evaluates the rates of early and late rectal toxicities in patients with prostate cancer receiving definitive or adjuvant three-dimensional conformal external beam radiation therapy and concurrent daily endorectal applications of amifostine. Endpoints include Radiation Therapy Oncology Group acute and late toxicity gradings, Expanded Prostate Cancer Index Composite self-assessment questionnaires, and proctoscopic examinations with scoring of mucosal damage measured before, during, and after treatment. Eleven patients have been enrolled to date; 10 have completed radiotherapy and three have been followed-up to 6 months. Two patients received 66 Gy to the prostatic bed post-prostatectomy; five patients received 74 Gy and three received 76 Gy to the prostate gland. In all patients, daily fractionation was 2 Gy, and 1 g of amifostine (50 mg/mL in 20 mL reconstituted saline) was administered endorectally 40 minutes before radiation delivery. Daily endorectal administration was well tolerated. To date, six patients have experienced grade 2 (Radiation Therapy Oncology Group) acute toxicities, all but one because of frequent bowel movements relieved by loperamide. The initial trial will proceed until 18 patients are accrued, at which time an interval evaluation of both early and late toxicity endpoints will be conducted.
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PMID:Clinical trial of endorectal amifostine for radioprotection in patients with prostate cancer: rationale and early results. 1472 42

Recent radiobiological analysis of the radiotherapy results for prostate cancer revealed that prostate carcinoma behaves as a late responding tissue, sharing an alpha/beta ratio lower than 2Gy. These findings suggest that hypofractionation may be more effective. Reduction of the overall treatment time could further increase response by abrogating the effect of rapid tumor repopulation. In the present study we report a conformal technique applied (to pelvis and prostate) for the treatment of high-risk prostate cancer, using hypofractionated and accelerated radiotherapy (3.4Gy x 15 consecutive fractions) supported with high-dose daily amifostine (1000mg subcutaneously) to protect normal tissues against early and late effects. The biological dose delivered to the prostate cancer by this HypoARC (hypofractionated accelerated radiotherapy with cytoprotection) technique is estimated to be 71.4Gy (alpha/beta= 1.5 Gy). The time-adjusted biological dose is estimated to 77-94 Gy. Amifostine tolerance was excellent. All seven patients recruited up to now have accomplished their treatment with grade 0-1 cystitis or diarrhoea (5/7 grade 0). The study is ongoing to assess efficacy and late effects of HypoARC.
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PMID:Conformal hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC) for high risk prostatic carcinoma: rationale, technique and early experience. 1551 Jun 17

Pelvic malignancies, including bladder, prostate, and gynecologic cancers, are typically treated with some form of radiation therapy. Reducing radiation-related toxicities in these patients is important for maintaining good quality of life as survival rates increase and also for directly affecting cure rates by reducing delays in radiotherapy. Amifostine (Ethyol) has been shown to reduce rectal bleeding in patients with prostate cancer treated with radiation therapy, prevent radiation-related dermatitis, and provide widespread mucosal protection without adversely affecting local or distant tumor control.
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PMID:Managing toxicities in pelvic malignancies. 1560 21