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)

The effect of taxol, an experimental antitumor drug, was studied in vitro on human prostatic cancer cells. Different concentrations of taxol, varying from 5 microM to 0.01 nM, were used. The effect of taxol was examined by light and electron microscopy. Taxol had a marked cytotoxic effect on prostatic cancer cells down to a 10 nM concentration of taxol when observed by light microscopy. However, by electron microscopy, the specific effect of taxol was seen even with a 1 nM concentration of taxol. Taxol induced the appearance of numerous round cells after a few days and, subsequently, progressive death of the tumor cells. Among the surviving tumor cells, large tumor cells were noted as well as many multinucleated tumor cells. By electron microscopy, the round tumor cells showed mitotic figures with a high amount of cytoplasmic microtubules. Nonmitotic cells were often multinucleated and contained a high number of cytoplasmic microtubules and microtubule-related structures. The results show that taxol, even at very low concentrations, has a highly cytotoxic effect on prostatic cancer cells; and when a very low concentration of taxol is used with no obvious cytotoxic effect at the light microscopic level, specific taxol-induced ultrastructural alterations can be observed.
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PMID:Morphological studies on the effect of taxol on cultured human prostatic cancer cells. 288 3

Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases of > or = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased by > or = 50% in 15 (65.2%) and by > or = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.
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PMID:Paclitaxel plus estramustine in metastatic hormone-refractory prostate cancer. 748 60

Estramustine phosphate is a unique antimitotic agent that binds to tubulin and microtubule-associated proteins. Preclinically, estramustine combined with other microtubule inhibitors, like vinblastine or paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), produced additive or greater antimitotic and cytotoxic effects. Clinically, the estramustine/vinblastine combination has significant activity in hormone-refractory prostate cancer. We have begun a phase I study of paclitaxel by 96-hour continuous infusion every 3 weeks combined with daily oral estramustine (600 mg/m2). Eighteen patients with refractory solid tumors have received paclitaxel doses ranging from 80 to 140 mg/m2. Grade 3 or 4 granulocytopenia occurred in one of seven and two of four patients treated at the 120- and 140-mg/m2 dose levels, respectively. The latter two patients experienced grade 3 mucositis and had mean plasma paclitaxel levels exceeding 0.1 mumol/L. Other toxicities, principally nausea and hepatic function abnormalities, have been mild. The apparent steady-state concentrations of paclitaxel 100 and 120 mg/m2 administered with estramustine are similar to those reported for single-agent paclitaxel administered as a 96-hour infusion at doses of 100 and 120 mg/m2. In contrast, at the 140 mg/m2 dose level, paclitaxel concentrations increased throughout the infusion, and steady state was not reached in three of the four patients treated. Objective responses have been observed in two of three patients with adenocarcinoma of the esophagus and in two patients with hormone-resistant prostate cancer and measurable soft tissue metastases. Two additional patients with prostate cancer have been treated with the estramustine/paclitaxel combination, one achieving a major response and the other stable disease. The recommended phase II dose for 96-hour infusional paclitaxel with daily oral estramustine is at least 120 mg/m2. Studies to determine the effect of estramustine on paclitaxel pharmacokinetics are continuing. The antitumor activity observed merits phase II studies of this combination in hormone-resistant prostate cancer and other malignancies.
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PMID:Phase I study of paclitaxel and estramustine: preliminary activity in hormone-refractory prostate cancer. 759 35

Microtubules, which are composed of polymerized tubulin dimers, play an important role in various cell functions. For example, they maintain cell shape, form mitotic spindles in M phase of cell cycle, and carry an axonal transport in nerve cells. Microtubules have also been an important target of cancer chemotherapy. Vinca alkaloids depolymerize microtubules, the mechanisms of which action have extensively been investigated recently. Clinical trials of vinorelbine (navelbine), a new semisynthetic vinca alkaloid, are ongoing in Japan. One of advantages of the drug is reduced risk of neurotoxicity. Estramustine may act on microtubule-associated proteins (MAPs) as well as tubulin. It shows additive or synergistic cytotoxicity preclinically when used in combination with vinblastine. This combination was active against hormone-refractory prostate cancer. Another novel drug rhizoxin, which has a similar mechanism of action to that of vinca alkaloids, is also a promising cytotoxic agent and is examined clinically in Europe. Taxanes, which include paclitaxel (Taxol) and taxotere, are interesting drugs because they promote polymerization of tubulin and stabilize microtubules. They show promising antitumor activity against breast, ovarian and lung cancers. Phase I and II trials are ongoing in Japan. Paclitaxel may also potentiate cytotoxicity of radiation. There are several mechanisms of resistance to microtubule-acting drugs. One is multidrug resistance mediated by P-glycoprotein. Other mechanisms include mutation of tubulin.
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PMID:[Microtubules and antineoplastic drugs]. 790 90

The ongoing phase I study reported here sought to determine the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin when given at specific times in combination with ifosfamide, mesna, and filgrastim. Patients in the trial included those with non-small cell lung cancer (three), breast cancer (two), metastatic adenocarcinomas of unknown primary site (two), prostate cancer (one), angioimmunoblastic lymphadenopathy (one), and mesothelioma (one). The median age of these 10 patients was 48 years (age range, 34 to 75 years) and none had received chemotherapy previously. Of the 12 patients who entered the study, 10 are eligible for analyses of toxicity and response. The only grade 4 toxicity observed was hematologic. One episode of neutropenic fever occurred in the 43 treatment cycles delivered so far, one patient experienced an ifosfamide-related change in mental state, and two patients developed reversible renal tubular acidosis. No other significant neurologic or renal toxicities have been observed. At dose level 1, the cycle-6 doses were delayed in one patient, and another patient required a 50% reduction of the ifosfamide dose during cycle 4 due to mental status change. At dose level 2, there were no dose reductions or delays due to side effects, although one patient withdrew due to disease progression. At dose level 3, dose delays only were required in six of 15 cycles. The response rate was 100%; four patients achieved a complete response (40%) and six a partial response (60%). This regimen appears to be tolerable and active at the dose levels completed thus far, with minimal nonhematologic toxicities.
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PMID:Phase I trial of dose-escalated paclitaxel and carboplatin in combination with ifosfamide and filgrastim: preliminary results. 904 27

Estramustine phosphate (EMP) is thought to form a chemical link between estradiol and non-nitrogen mustard. An estramustine-binding protein has been isolated in prostate, breast, and brain cancers as well as in malignant melanoma cells. Estramustine phosphate's ability to bind to microtubular-associated proteins and to interfere with mdr-mediated drug efflux are thought to result in its enhancement of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) activity in cell lines and in its ability to affect hormone-resistant prostate cancer. This phase I study administered combined paclitaxel and EMP to 25 women with ovarian, breast, and other tumors and assessed efficacy and toxicity. Estramustine phosphate was administered at two dose levels, 900 or 1,200 mg/m2 daily on days 1, 2, and 3 in 3-week cycles. On day 3, paclitaxel (150, 180, 210, or 225 mg/m2) was given concomitantly by 3-hour infusion. Therapeutic effects were noted in all patients. Partial responses were noted in three of eight patients with breast cancer who had failed to improve on paclitaxel alone. Three other patients experienced prolonged stable disease. Only moderate toxicities were noted until EMP levels of 1,200 mg/m2 were reached. At these dose levels, gastrointestinal toxicities became more prominent. The addition of EMP to paclitaxel allowed patients to receive paclitaxel for longer periods, and may have enhanced the therapeutic effects of paclitaxel. If so, the mechanisms of such enhancement warrant investigation. The two drugs may work on different aspects of microtubular function, for example, or may reduce efflux of paclitaxel in P-glycoprotein overexpressed tumors.
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PMID:Response to estramustine phosphate and paclitaxel in patients with advanced breast cancer: a phase I study. 907 37

We previously developed a novel and effective therapy for hormone-refractory prostate cancer using the agents estramustine and etoposide. Although neither of these agents alone is effective in the treatment of advanced, hormone-refractory prostate cancer, we predicted their activity when used in combination based on preclinical assays, and then demonstrated their effectiveness in a phase I-II clinical trial, where they were shown to produce a 50% complete and partial response rate in patients with bidimensionally measurable disease. In preclinical studies, we had demonstrated that estramustine and etoposide interact with the nuclear matrix, which is the site of DNA replication. Expanding these investigations, we determined that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule inhibitor, interacts with estramustine and etoposide, and the combination of these three agents had significant preclinical activity against androgen-independent prostate cancer cells. These studies led us to conduct a phase II clinical trial of paclitaxel, estramustine, and etoposide in patients with hormone-refractory prostate cancer. Preliminary results demonstrate that this is an active regimen, with 57% of patients demonstrating a response to therapy as measured by a decrease in pretreatment prostate-specific antigen levels of greater than 50%.
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PMID:Paclitaxel, estramustine, and etoposide in the treatment of hormone-refractory prostate cancer. 934 27

bcl-xL is an antiapoptotic protein that shares sequence homology with bcl-2 and seems to convey chemoresistance in many human tumor cell lines. bcl-xL protein is expressed at a 3-fold higher level in PC-3 cells than it is in LNCaP cells. Taxol causes apoptosis in both these cell lines, as measured by the formation of DNA ladders and by the observation of typical cellular morphological changes (chromatin condensation and nuclear fragmentation) after 4', 6-diamidino-2-phenylindole staining. Overexpression of bcl-2 in LNCaP cells did not prevent Taxol-induced apoptosis. Treatment of LNCaP cells with 10 nm Taxol led, after 24 h, to relatively specific and almost total down-regulation of bcl-xL protein in the absence of alteration of bax, bak, or bcl-2 levels. This change was paralleled by a similar decrease in the level of bcl-xL mRNA, as demonstrated by reverse transcription-PCR. The level of glyceraldehyde-3-phosphate dehydrogenase mRNA was not changed. In PC-3 cells, 48 h were required for both maximal bcl-xL protein down-regulation and cellular apoptosis. In contrast, treatment of LNCaP cells with estramustine induced apoptosis, but this was not associated with any change in the intracellular level of bcl-xL or bax protein. Instead, relatively specific 2-fold up-regulation of the proapoptotic protein bak was observed. In PC-3 cells, cellular apoptosis induced by estramustine was bak independent. These results augment our understanding of the importance of bcl-xL in prostate cancer and suggest that appropriate manipulation of cytotoxic chemotherapeutic agents may favorably alter the balance between pro- and antiapoptotic proteins in this tumor.
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PMID:Taxol and estramustine-induced modulation of human prostate cancer cell apoptosis via alteration in bcl-xL and bak expression. 981 95

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in men in the United States. In 1997 it was estimated that more than 41,000 men died of this disease. Treatment of metastatic disease remains palliative, with androgen ablation used as first-line therapy. After failure of androgen ablation, chemotherapy can now be used to induce a remission in many men. Treatment regimens that include paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have been particularly successful in treating hormone-refractory prostate cancer in the phase II setting. We have conducted a trial of estramustine 280 mg orally three times per day for 14 days combined with etoposide 50 mg/m2/d (in general, one 50-mg tablet twice a day) for 14 days, with paclitaxel 135 mg/m2 over 1 hour on day 2. This regimen is repeated every 21 days for a maximum of six cycles. Patients responding to therapy are then given a break and re-treated at physician discretion. On preliminary analysis, 24 of 38 patients demonstrated a decline in pretreatment prostate-specific antigen of more than 50% (63%). The regimen was well-tolerated and only seven patients demonstrated grade 3 or 4 neutropenia. Further analysis is ongoing.
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PMID:Paclitaxel in the treatment of hormone-refractory prostate cancer. 1019 Jul 91

Most prostate cancers eventually develop resistance to hormonal therapy and chemotherapies. Many mechanisms for resistance to chemotherapy have been identified. Mutations or inactivation of the p53 suppressor gene and overexpression of bcl-2 are among such mechanisms. Mutations in the p53 gene can lead to resistance to certain chemotherapy agents, and such mutations are seen more often in metastatic than in primary prostate cancers. Thus, agents that are active in the setting of mutated p53 may have some advantage in prostate cancer. Overexpression of bcl-2 occurs frequently in prostate cancer and is associated with both hormonal therapy and chemotherapy resistance. In experimental systems, bcl-2 overexpression occurs after androgen deprivation and transfection of bcl-2 into sensitive cell lines makes them resistant to chemotherapy and hormonal therapies. Bcl-2 can be inactivated by phosphorylation as occurs with taxanes. The retinoids, as a class, can inhibit the growth of resistant cell lines that overexpress bcl-2, and the combination of interferon (IFN) and cis-retinoic acid (CRA) demonstrated increased antitumor activity. In our cell line model the combination of IFN and CRA greatly enhanced the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on these observations, we conducted a phase I/II trial of CRA and IFN-alpha in patients with biochemical recurrence of prostate cancer. Twenty-six percent achieved a decrease of prostate-specific antigen (PSA), which was correlated to elevated serum transforming growth factor-beta. We then conducted a phase I trial of 13-CRA, IFN-alpha, and escalating doses of paclitaxel. Eighteen patients were treated with 1 mg/kg CRA and 1x10(6) unit IFN on days 1 to 4 and paclitaxel at doses from 100 to 175 mg/m2. Eleven patients received the 175 mg/m2 paclitaxel dose. Two patients in the phase I study achieved partial responses (one cervix and one prostate cancer). We subsequently initiated a phase II study of 13-CRA, IFN-alpha, and paclitaxel in hormone refractory prostate cancer. For entry patients must show progressive disease after androgen ablation. To test the mechanism of action, we are assaying peripheral blood monocytes and, when possible, tumor tissue for bcl-2 expression. As our understanding of the mechanisms of tumor resistance to chemotherapy improves, we will be able to design better approaches in treatment targeted to overcome the mechanisms of resistance.
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PMID:Overcoming bcl-2- and p53-mediated resistance in prostate cancer. 1019 Jul 92


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