Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a member of the taxanes, has been shown to have antitumor activity in a wide variety of cancers, such as breast cancer and ovarian cancer. Paclitaxel also has antitumor activity in certain previously relatively unresponsive tumors, such as lung, head and neck, esophageal, and bladder cancers. The optimal dose for each tumor has not been well defined. While 3-hour infusion appears to be the most convenient, studies of both longer and shorter infusions are in progress. Any incremental benefit of higher dose or longer schedule will need to be evaluated on the basis of the higher costs and toxicities. The results of many initial studies using combination chemotherapy with paclitaxel have generated considerable enthusiasm, but careful comparison studies and evaluation of toxicities are needed. Additional roles of paclitaxel include its ability to act synergistically with radiotherapy, and thus possibly help improve the local control of tumors, such as head and neck, esophageal, bladder, and lung cancers. Studies testing the role of the taxanes in neoadjuvant therapy before radiotherapy or surgery are just beginning. Paclitaxel is thus one of the very important new agents in the treatment of cancer, and further work is needed to define its optimal use.
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PMID:Paclitaxel in head and neck and other cancers: future prospects. 904 28

This report summarizes the clinical experience of investigators at the istituto Nazionale Tumori in Milan, Italy, with intravenous paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) infused over 3 hours plus bolus doxorubicin in women with untreated breast cancer. The overall experience indicates that the combination of paclitaxel/doxorubicin is a very active primary chemotherapy for stage IV breast carcinoma and is associated with manageable toxicity. The results suggest that the incidence of cardiotoxicity and duration of neutropenia can be reduced by limiting the total cumulative dose of doxorubicin to 360 mg/m2 and by adding granulocyte colony-stimulating factor to the primary chemotherapeutic regimen. In addition, the study indicates that continuous treatment of responding patients with single-agent paclitaxel after this combination increases the patients' chances of complete response. These favorable results indicate that this regimen could be a very effective treatment option as adjuvant or neoadjuvant chemotherapy in women with early stage operable breast cancer as well as those with advanced breast cancer.
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PMID:Experience at the Istituto Nazionale Tumori with paclitaxel in combination with doxorubicin in women with untreated breast cancer. 907 31

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

The first phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in breast cancer was completed at M.D. Anderson Cancer Center, and included 25 patients with metastatic breast cancer who had been previously treated with one chemotherapy regimen. Fourteen of these patients achieved a major objective response; the median response duration was 9 months, and the median survival time, 20 months. Additional trials showed that paclitaxel maintained its antitumor efficacy in patients with two and three prior chemotherapy regimens, including patients with anthracycline-resistant breast cancer. Combination therapy with doxorubicin showed that this combination was effective, although with the long infusion duration used for both agents, sequence-dependent toxic interactions were encountered. In combination with vinorelbine, dose-limiting toxicity included neutropenic fever and neuropathy. High-dose single-agent paclitaxel is currently being explored in the management of inflammatory breast cancer and as part of neoadjuvant chemotherapy for stages II and III operable disease.
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PMID:The University of Texas M.D. Anderson Cancer Center experience with paclitaxel in breast cancer. 907 38

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. (90)Y-labeled DOTA-peptide-ChL6 ((90)Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and (90)Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving (90)Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before (90)Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after (90)Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with (90)Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to (90)Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with (90)Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with (90)Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.
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PMID:Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts. 910 94

The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) to further examine the agent's potential in the treatment of advanced breast cancer. Efficacy and tolerability studies of paclitaxel as single-agent therapy were undertaken, along with parallel investigations of quality-of-life parameters. The studies examined the effects of 96-hour infusion schedules of paclitaxel and are currently assessing the feasibility of a weekly 1-hour infusion schedule. Researchers at MSKCC also compared the results of a variety of two- and three-drug paclitaxel-containing regimens to determine possible synergism and better define safety profiles. They examined the combination of paclitaxel and edatrexate, as well as a promising combination of paclitaxel and a monoclonal antibody directed at growth factor receptors. The latter ongoing trial will include both laboratory studies that examine possible cellular mechanisms for the combination's observed synergy and a clinical trial that combines paclitaxel with a monoclonal antibody directed against the epidermal growth factor. In conclusion, the investigators discuss the optimal integration of paclitaxel into doxorubicin/cyclophosphamide (Cytoxan, Neosar)-based adjuvant therapy for node-positive stage II-III resectable breast cancer.
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PMID:Paclitaxel for breast cancer: the Memorial Sloan-Kettering Cancer Center experience. 911 Mar 39

The extensively studied agent docetaxel (Taxotere) has shown marked clinical activity in the treatment of anthracycline-resistant breast cancer. Phase I trials indicate that toxicities, such as mucositis and neutropenia, limit the administration of docetaxel to shorter perfusion schedules. Pharmacokinetic studies have shown that docetaxel's clearance by hepatic metabolism is correlated with a marked increase in risk of toxicity in patients with impaired liver function. Nevertheless, studies of docetaxel as front-line therapy for breast cancer were initiated because of its good activity against tumors in early studies and its close relationship to paclitaxel (Taxol), an agent with proven efficacy. Phase II studies have demonstrated excellent activity for docetaxel as a single agent, with an overall response rate of 61% in trials of a 100-mg/m2 dose. A phase III study is currently comparing docetaxel with paclitaxel as single-agent therapy. Docetaxel is expected to provide a better response rate but a higher incidence of neutropenia. The agent shows promise in adjuvant therapy, with very high response rates in anthracycline-resistant patients. Preliminary results of tests using docetaxel in combination with doxorubicin show high objective response rates but low complete response rates; early results suggest that this combination may have some advantages over paclitaxel/doxorubicin.
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PMID:The international experience with docetaxel in the treatment of breast cancer. 911 Mar 41

Overexpression by the HER2 gene plays a significant role in breast cancer pathogenesis, and the phenomenon is commonly regarded as a predictor of a poor prognosis. HER2 overexpression has been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoruracil) and anthracyclines. Studies of patients with advanced disease demonstrate that, despite the association of HER2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to taxanes were greater than three times those of HER2-negative patients. Further studies in preclinical models used combination therapy for breast cancer cells that overexpress HER2, and the use of agents that interfere with HER2 function plus paclitaxel (Taxol) resulted in significant antitumor effects.
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PMID:HER2 overexpression and paclitaxel sensitivity in breast cancer: therapeutic implications. 911 Mar 42

The recognition of paclitaxel's (Taxol) activity and non-cross-resistance with doxorubicin (Adriamycin) in the treatment of metastatic breast cancer has motivated study of the agent in the adjuvant setting. However, the ideal means of incorporating this new agent is not yet known. In stage IV disease, exciting results have been seen with combinations of doxorubicin plus paclitaxel, and this approach is being tested as adjuvant treatment. An alternative approach that has produced superior results with other non-cross-resistant regimens is sequential administration of the combination agents. Based on prior clinical trials, we tested sequential dose-dense therapy with high-dose doxorubicin, followed first by paclitaxel and then by cyclophosphamide (Cytoxan) for high-risk operable breast cancer. This regimen was associated with marked toxicity but was nonetheless tolerable and resulted in promising relapse-free survival. This regimen is now being compared to high-dose chemotherapy with autologous stem cell support for women with operable breast cancer, metastatic to four to nine axillary lymph nodes.
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PMID:Sequential dose-dense adjuvant therapy with doxorubicin, paclitaxel, and cyclophosphamide. 914 85


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