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

Mitoxantrone is an anthraquinone antineoplastic agent with structural similarities to doxorubicin. It has a mechanism of action similar to the anthracyclines. Its primary elimination route is hepatic metabolism (only seven percent renal excretion) and it has a terminal half-life of approximately 40 hours. Mitoxantrone has significant activity in the treatment of metastatic breast cancer, acute leukemias, and non-Hodgkin's lymphoma. Some activity is reported in head and neck cancer, Hodgkin's, myeloma, bladder cancer, prostate cancer, non-small-cell lung cancer, and liver cancer. There is a suggestion of incomplete cross-resistance between mitoxantrone and the anthracyclines in certain neoplasms. Some activity is reported with mitoxantrone in patients refractory to the anthracyclines in breast cancer, acute leukemias, and non-Hodgkin's lymphomas. The usual doses used in solid tumors and in lymphomas are mitoxantrone 12-14 mg/m2 iv q3-4wk and in leukemias is mitoxantrone 12 mg/m2/d X 5 d iv for initial induction.
 ...
PMID:Mitoxantrone. 351 24

LNCaP, DU145, and PC3 prostate carcinoma cells secrete the 27-kDa soluble Fas ligand (sFasL) into their local environment. sFasL arises from the 40-kDa membrane-bound form (mFasL), which can be found on the cell surface in the LNCaP line, as demonstrated by monoclonal antibody staining. mFasL was also found in extracts of all three cell lines, as demonstrated by Western blotting. FasL mRNA was detected not only in the cell lines, but in the normal prostate as well. sFasL protein could also be detected immunohistochemically in prostate secretions and in human semen. Cleavage of mFasL to sFasL could be inhibited by several matrix metalloprotease inhibitors without a change in the cellular levels of FasL. Prostate-derived sFasL is biologically active, as demonstrated by its induction of apoptosis in Fas-positive Ramos cells, which was detected by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Mitoxantrone induces cellular apoptosis in all three prostate cancer cell lines. Mitoxantrone treatment and doxorubicin treatment also cause up-regulation of Fas, the cell surface receptor for FasL, in LNCaP cells, but not in DU145 or PC3 cells. Furthermore, the up-regulation of Fas expression by mitoxantrone at a high concentration was potentiated by hydrocortisone. When FasL interacts with its Fas, the Fas-bearing cell undergoes apoptosis. When LNCaP cells were treated with mitoxantrone and incubated with an anti-FasL monoclonal antibody, apoptosis was partially blocked. This not only further suggests that the sFasL is biologically active, but that the up-regulation of Fas in the presence of sFasL accounts, in part, for the cytotoxicity of mitoxantrone.
 ...
PMID:Fas ligand is constitutively secreted by prostate cancer cells in vitro. 967 59

Prostate cancer is the most common tumor and second most common cause of cancer death in American men. Advanced prostate cancer patients commonly have painful skeletal bony metastases. Although hormonal therapy is very effective initially, hormone-refractory prostate cancer may be associated with bone pain and other symptoms such as urinary obstruction. Aside from oral and parenteral non-narcotic and narcotic medications, several recent FDA-approved outpatient medications are effective for palliation of painful bony metastases. Mitoxantrone chemotherapy in combination with glucocorticoids and the radioisotopes strontium-89 and samarium-153-lexidronam are now available. Urologic nursing personnel should be familiar with these new and complementary modalities.
 ...
PMID:Prostate cancer in the late 1990s: hormone refractory disease options. 1063 63

Adenocarcinoma of the prostate is the most prevalent neoplastic disease in men and continues to be a major cause of morbidity and mortality. Death from prostate cancer is associated with objective and biochemical progression following hormonal manipulations often described as hormone refractory prostate cancer (HRPCA). Therapy for HRPCA is primarily palliative and therapeutic efficacy has to be balanced against potential treatment-related side effects. Therapeutic efficacy may be assessed by evaluating the percentage of patients obtaining a PSA decline of > 50%, evaluating the response of bidimensionally measurable disease or by improvements in quality of life assessments. The most effective cytotoxic therapies at the present time seem to be combinations of estramustine phosphate with taxanes and etoposide. Regimes employing ketoconazole with estramustine, vinblastine or bisphosphonates seem to be worthy of further evaluation. Mitoxantrone has an impressive palliative effect in patients, particularly when combined with hydrocortisone. Oral chemotherapeutic regimens with a combination of estramustine phosphate, cyclophosphamide and prednisone appear to offer a less toxic alternative. For the future we need prospective randomized clinical phase-III studies, prognosticators identifying patients as being at high or low risk who might benefit from different therapeutic approaches and generally binding eligibility and response guidelines in order to be able to compare trials of different therapeutic approaches.
 ...
PMID:Current status of cytotoxic chemotherapy in hormone refractory prostate cancer. 1122 70

(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.
 ...
PMID:Mitoxantrone: new indication. More risky than beneficial in advanced prostate cancer. 1171 79

Recently, several important studies have validated prostate-specific antigen (PSA) as a reliable measure of response to chemotherapeutic treatment in advanced hormone-refractory prostate cancer. Furthermore, although chemotherapy in this setting has always been considered palliative, several analyses of recent clinical trials have demonstrated a significant association between declines in PSA values of 50% or more and prolonged survival. Mitoxantrone, in combination with prednisone, has been shown to provide significant palliation and improved quality of life. The use of combinations of chemotheraputic agents also seems to provide significantly superior objective and subjective responses compared with single-agent regimens. In particular, estramustine has been shown to synergize many of the agents used in prostate cancer treatment and has been demonstrated to provide significant palliation and decline in PSA levels in combination with vinblastine, vinorelbine, etoposide, paclitaxel, and docetaxel. The results of several important trials of the taxanes both as single agents and in combination with estramustine have been completed in the past year and have demonstrated that these agents are very effective in the treatment of hormone-refractory prostate cancer.
 ...
PMID:Recent advances in chemotherapy for advanced prostate cancer. 1208 41

Prostate cancer that grows despite castrate levels of testosterone and that no longer responds to any form of hormonal manipulation and for which nonhormonal approaches are required, can be precisely defined as hormone-refractory prostate cancer (HRPC). Until recently, there has been no standard chemotherapeutic approach for HRPC. In this article recent advances in the treatment of HRPC using chemotherapeutic regimens are critically reviewed. We performed a MEDLINE search of the published reports from 1995 to 2002 including chemotherapy in the treatment of HRPC. We critically reviewed a total of 84 clinical trials, of which only 6 were phase III trials, most of the studies being phase II trials. Various chemotherapeutic agents have been used. To date, the major benefits of chemotherapy in the treatment of HRPC are palliative in nature, in terms of reduction of pain and use of analgesics and improvement of performance status, as followed in the most recent trials. There is a promising activity of new drug combinations, such as vinca alkaloids and taxanes in association with estramustine. Mitoxantrone, although with a limited activity, has been shown to provide improvement in pain and quality of life for the patients. Several studies suffer from methodological deficits, such as small number of patients, heterogeneity of enrolled groups or no definitive response criteria. Further phase III studies are necessary to better evaluate the efficacy of the different regimens.
 ...
PMID:Role of chemotherapy in hormone-refractory prostate cancer. Old issues, recent advances and new perspectives. 1256 8

As no treatment has been demonstrated to prolong survival in hormone-refractory prostate cancer, it was interesting to define the current management of these patients. This survey was designed to identify the criteria used to define hormonal escape, to more clearly define the treatment modalities at this stage of the disease and to evaluate the various therapeutic approaches used. A self-administered questionnaire accompanied by 3 clinical cases was sent by mail to all French urologists registered with the AFU. Three hundred and one (31%) questionnaires were returned. The diagnosis of hormone-refractory cancer was based on the presence of clinical signs or elevated PSA levels in 61% of cases. 65% of urologists reported that they changed treatment as soon as symptoms appeared. The objectives of treatment were improvement of quality of life in 95% of cases and relief of symptoms in 90% of cases. The first-line treatment after hormonal escape is very predominantly (at least 90% of cases) multiple hormonal manipulations. Chemotherapy or referral of patients to an oncologist is performed by more than one third of doctors as second-line treatment (35% of cases) and in almost all cases as third-line treatment (87% of cases). Mitoxantrone-prednisone is the combination chemotherapy most frequently reported in this survey (2 out of 3 doctors). These data illustrate the application by French urologists of the current CCAFU guidelines (Oncology Committee of the French Urology Association) for hormone-refractory prostate cancer.
 ...
PMID:[Diagnosis and management of advanced hormone-refractory prostate cancer: results of a practice survey on 301 French urologists]. 1521 32

Combination therapy including antisense oligonucleotides (ODNs) with traditional chemotherapeutic agents offers potential benefits by increasing the effectiveness of the chemotherapeutics, reducing their effective dosage, and simultaneously reducing toxicity. Previously we have reported that antisense ODNs specific for transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR) (MR1 and MR2, respectively), are effective against the PC-3 in vitro and in vivo prostate cancer models. In this series we evaluated these antisense ODNs in various combinations and treatment cycles with paclitaxel (Taxol), cyclophosphamide (Cytoxan), mitoxantrone, carboplatin, cisplatin, and oxaliplatin in order to identify synergistic effects.We found that when either of the ODNs were simultaneously administered with Taxol, no synergistic activity was noted. However, when sequentially administered in a series 1 d apart, a pretreatment with the ODN directed against TGF-alpha (6.64 microm) followed by Taxol (5 nm) had significantly (p <0.001) greater activity than these agents similarly administered in the reverse order or simultaneously. When Cytoxan was administered in sequence with both ODNs significantly increased growth inhibition was obtained compared to when Cytoxan was administered alone. A 1 d treatment of PC-3 cells with Cytoxan followed the next day with MR1 was significantly more effective (p <0.0001). The reverse order, a pretreatment with MR1 followed by Cytoxan, also resulted in significant additional inhibition (p=0.0004). Similarly sequenced, MR2 followed by Cytoxan, was also significantly more effective (p=0.0014) than Cytoxan treatment alone. For mitoxantrone, which was administered in combination therapy with ODNs: mitoxantrone with MR1 was significantly more inhibitory than the combination of both MR1 and MR2 ODNs (p=0.006) and also mitoxantrone administered alone (p=0.0012). Mitoxantrone administered with MR1 was not significantly different from mitoxantrone given in combination with MR2. Although mitoxantrone and MR2 was statistically (p=00015) more inhibitory than mitoxantrone alone, this combination was barely more effective (p=0.04) than the MR1 ODN administered alone.
 ...
PMID:Synergistic effects of combination therapy employing antisense oligonucleotides with traditional chemotherapeutics in the PC-3 prostate cancer model. 1557 18

Mitoxantrone, a synthetic anthracenedione, was developed in the 1980s as a doxorubicin analogue in a program to find a cytotoxic agent with decreased cardiotoxicity compared with doxorubicin. It was approved by the FDA in 1987 for the treatment of adult acute myeloid leukemia and in 1996 for symptomatic hormone-refractory prostate cancer. In 2000, mitoxantrone was approved by the FDA for the treatment of worsening relapsing-remitting multiple sclerosis (MS), secondary progressive MS, and progressive-relapsing MS. Mitoxantrone is taken up rapidly by tissues, from which it is released slowly, and the terminal half-life ranges from 8.9 hours to 9 days. The highest concentrations of the drug are typically found in the thyroid, liver, and heart, and the drug persists in the body for as long as 272 days. Mitoxantrone is effective in reducing disease progression through a variety of different mechanisms of action. For example, it suppresses the proliferation of T cells, B cells, and macrophages. It impairs antigen presentation and decreases the secretion of proinflammatory cytokines. Mitoxantrone enhances T-cell suppressor function and inhibits B-cell function and antibody production. Finally, it inhibits macrophage-mediated myelin degradation. Compared with interferon betas, mitoxantrone has a broad range of actions and has effects on many different types of immune cells.
 ...
PMID:Mechanism of action of mitoxantrone. 1562 64


1 2 Next >>