Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with metastatic breast cancer will receive 4-5 cycles of induction chemotherapy on one of the ongoing Medicine Branch protocols. Patients achieving at least a partial response, and who do not have evidence of bone marrow involvement and who do not have metastatic bone disease, will undergo PBSC and bone marrow harvest when hematologic recovery has occurred. Patients who have not achieved a PR, but who are responding to therapy, may be treated with additional cycles of therapy in an attempt to achieve a PR. Such patients will be eligible for transplant if a PR is obtained. 70% of the bone marrow and PBSC will be cryopreserved. The CD34+ subpopulation from the remaining 30% of the bone marrow and PBSC harvest will be obtained using an anti-CD34+ antibody and immunoabsorption column. The bone marrow and peripheral blood CD34 cells will be transduced with a retroviral vector expressing the human MDR-1 cDNA. Patients with positive bone scans or histologic evidence of bone marrow involvement will be excluded from the gene transfer component of the protocol. The MDR-1 transduced CD34 cells will be reinfused along with the non-transduced bone marrow and PBSC into patients following high dose ICE chemotherapy. Serial peripheral blood and bone marrow samples will be obtained to study hematopoietic reconstitution with MDR-1 transduced cells. Patients with residual or progressive disease after ABMT will be treated with taxol or vinblastine. In these relapsed patients, peripheral blood and bone marrow samples will be obtained to study whether chemotherapy amplifies the proportion of hematopoietic cells containing the MDR-1 provirus. We will monitor the nadir blood counts of each patient receiving salvage chemotherapy for evidence of myeloprotection and correlate this data with changes in the mean proviral copy number. Sites of relapsed tumor will be biopsied to test for the presence of the MDR-1 provirus.
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PMID:Retroviral mediated transfer of the human multidrug resistance gene (MDR-1) into hematopoietic stem cells during autologous transplantation after intensive chemotherapy for metastatic breast cancer. 752 2

For the integration of new cell biological prognostic factors in daily clinical practice, we need to know not only their prognostic power with respect to prediction of relapse free and overall survival, but also their possible relation to response to endocrine therapy or chemotherapy in order to select adequate treatment for each patient. A large number of cell biological parameters are currently available to predict the prognosis of patients with breast cancer, but it is still difficult to predict the response to treatment accurately. A valuable prognostic factor can be a worthless predictive factor for endocrine therapy or chemotherapy, and vice versa. High tumour levels of ER, PGR, AR and PS2 protein predict a relatively good response to endocrine therapy, whereas EGFR positivity, HER2/neu positivity, aneuploidy, high proliferation indices and possibly high u-PA levels indicate a good chance of a poor response to endocrine therapy in metastatic breast cancer. With respect to chemotherapy, a high proliferation rate and HER2/neu amplification predict a good response to therapy in metastatic disease, whereas MDR gene expression and possibly c-myc amplification are related to a worse response. In conclusion, the newer cell biological parameters can be used to select high and low risk patients and type of systemic treatment and can be used as targets for new treatment modalities.
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PMID:Prognostic factors and response to therapy in breast cancer. 801 96

A large number of cell biological parameters are currently available to predict the prognosis of patients with breast cancer, but it is still difficulty accurately to predict the response to treatment. A valuable prognostic factor can be a poor predictive factor for response, and vice versa. High tumor levels of ER, PgR, AR and pS2 predict a relatively good response to endocrine therapy, while EGF-R positively, HER2/neu positivity, aneuploidy, high proliferation indices and possibly high uPA levels indicate a high chance of poor response to endocrine therapy in metastatic breast cancer. With respect to chemotherapy, a high proliferation rate and HER2/neu amplification predict a good response to therapy in metastatic disease, while MDR gene expression and possibly c-myc amplification are related to a worse response. In conclusion, the newer cell biological parameters can be used to select high and low-risk patients, type of systemic treatment, and as targets for new treatment modalities.
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PMID:Cell biological factors associated with the response of breast cancer to systemic treatment. 848 34

The introduction of new drugs may offer significant hope for improvement in the treatment of breast cancer. They include new cytotoxic agents such as Taxanes, Topoisomerase inhibitor, MDR modulator, new hormone such as 3rd generation nonsteroidal aromatase inhibitor, pure antiestrogen for patients with refractory metastatic breast cancer and new bisphosphonates for those who have metastases to bone. Therefore, some reports evaluating such new drugs were reviewed. Japanese studies revealed response rate of Taxanes in the treatment of metastatic breast cancer as follows; Six out of 22 (27%) with 1 CR for 24 hours infusion, 21 out of 52 (34%) with 2 CR for 3 hours infusion of paclitaxel respectively, 21 out of 31 (41%) with 2 CR for 1 hour infusion, and 32 out of 72 (44%) with 5 CR for 1 hour infusion of Docetaxel, In addition, the MTD of the combination was reached at dose level with 60 mg/sqm of Docetaxel and 400 mg/sqm of cyclophosphamide. As regards hormone therapy, thirty four out of 176 (19%) with 5 CR were observed in phase II study of Fadrozol but results from the phase II study of 3rd generation aromatase inhibitor is not yet accomplished in Japan. However, any european reports did not show a difference in response rate in patients with tamoxifen refractory breast cancer between newer aromatase inhibitor and megasterol, and a good choice of hormones in the treatment of metastatic breast cancer appears to be difficult.
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PMID:[New drugs in metastatic breast cancer--1997]. 935 Feb 35

Idarubicin (4-demethoxydaunorubicin) (IDA) is a daunorubicin analogue with substantial activity in hematologic malignancies and solid tumors. Among several reasons, IDA is of interest because of its main metabolite derivative, the C-13 alcohol analogue, idarubicinol (IDOL). Previous studies have suggested that IDOL, unlike other anthracycline metabolic derivatives, possesses a striking growth-inhibitory activity in tumor cell lines. This suggests that IDOL, like IDA could be useful in circumventing MDR. IDA is bioavailable in an oral dosage form. After oral administration of IDA to the patients, the concentration of IDOL quickly exceeds that of IDA and is retained in the plasma for a longer period. Hence, administration of IDA to cancer patients results ina much greater overall exposure of the tumor to IDOL than to the parent compound. At the Oncology Center (CRO) in Aviano we performed a dose-finding and pharmacokinetic (PK) study of chronic daily oral IDA with intrapatient escalation in patients with metastatic breast cancer (MBC). All the patients were pretreated with anthracyclines (the cumulative dose was 530 mg and 264 mg, respectively, for epirubicin and (DOX) and had at admittance a PS < or = 2 and a left ventricular ejection fraction > 50%. IDA (1 mg capsules) was administered orally twice a day for 21 days every two weeks. Treatment was continued at escalating doses until progression or intolerance. Twenty-five patients were enrolled. MTD has not yet been reached and clinical results are reported in Table 1. Treatment was well-tolerated in all but one patient (300 ANC at day 28). Three patients had tox G3 ANC for more than three weeks after 3, 6, and 7 mg doses, respectively. Two of them stopped chemotherapy after 1 cycle and 1 patient stopped after 2 cycles (6 mg doses). Despite previous treatments with anthracyclines (the mean cumulative dose before entering the study was 530 and 264 mg, respectively, for epirubicin and DOX) no cardiotoxicity due to IDA treatment was observed. This trial demonstrates the feasibility of chronic daily IDA administration. At the dosage reported, treatment was generally well tolerated. The PK findings (high IDOL concentrations) and the unexpected G4 myelotoxicity in patients with the highest IDOL plasma concentrations suggest that IDOL is clinically relevant.
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PMID:Pharmacology of chronic oral daily administration of idarubicin. 940 45

Chemotherapy resistance is a major problem in the management of patients with breast cancer. Clinical resistance of solid tumors such as breast cancer is likely to be multifactorial and heterogeneous. Usually, patients refractory to chemotherapy exhibit resistance to multiple cytotoxic agents of different structure (and often function). A comparable experimental phenomenon has been termed multidnug resistance or MDR. MDR can be caused by various molecular mechanisms. One of these mechanisms is overexpression of MDR1/P-glycoprotein, which cna be expected in around 30-40% of primary and 50% of metastatic breast cancers. Preliminary evidence suggests that P-glycoprotein-positivity is associated with poor treatment outcome in both primary and advanced breast cancer. Studies of MDR reversal in metastatic breast cancer have generally yielded negative results. Recently, however, we found dexverapamil to be able to induce partial remissions to epirubicin in 4/23 patients (17%) with metastatic breast cancer refractory to the same dose and schedule of epirubicin alone. Dexverapamil did not increase the toxicity or the area under the plasma concentration-time curve of epirubicin. More carefully designed and conducted studies are needed to conclusively determine the clinical relevance of various resistance mechanisms in breast cancer and whether chemosensitizers such as dexverapamil or cyclosporins are able to enhance chemotherapy efficacy in this tumor.
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PMID:Chemotherapy resistance in breast cancer. 970 89

Most patients relapse after high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT) for metastatic breast cancer. Further chemotherapy immediately after hematopoietic recovery from ASCT is not given for fear of irreversibly damaging the newly engrafted stem cells. In a pilot chemoprotection trial, autologous CD34+ cells from patients with metastatic breast cancer were exposed to a replication-incompetent retroviral vector carrying MDR-1 cDNA and then reinfused after HDCT. Immediately on recovery, patients received multiple courses of escalating dose paclitaxel. All of the 10 patients tolerated reinfusion of modified cells without any toxicity and had myeloid engraftment within 12 days (range, 11-14). The bone marrow cells of three patients contained vector MDR-1-positive cells only at the time of the first course of posttransplant paclitaxel, indicating that the MDR-1 vector-modified cells had only short-term engrafting potential. A total of 83 courses of paclitaxel were administered starting at a median of 30 (range, 21-32) days from ASCT. The median dose of paclitaxel was 225 mg/m2 and the median interval between paclitaxel cycles of therapy was 21 (range, 20-41) days. Five of the six CR patients were able to receive all of the 12 courses of paclitaxel. Three patients who had achieved less than a complete response to the HDCT (2 patients) and partial response (1 patient) were converted to complete clinical responses during the 12 cycles of paclitaxel. No delayed toxicity or bone marrow failure was noted in these patients with a median follow-up of 2 years from ASCT. This is the first study of chemotherapy immediately after transplantation with autologous CD34+ cells. These data indicate that paclitaxel can be safely administered immediately after ASCT without any delayed toxicities. Paclitaxel given immediately after ASCT can further improve the response to pretransplant chemotherapy in patients with advanced breast cancer.
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PMID:Chemotherapy immediately following autologous stem-cell transplantation in patients with advanced breast cancer. 982 34

Liposomal annamycin (L-AN) has shown antitumor activity in preclinical studies. It may selectively target tumors and bypass MDR-1 resistance. A total of 13 women with doxorubicin-resistant breast cancer were treated on this phase II study. The median number of prior chemotherapy regimens was two, and six patients had two or more organ sites of involvement. L-AN was administered at 190-250 mg/m(2) as an i.v. infusion over 1-2 h every 3 weeks. No responses were observed. Of the 13 patients, 12 had clear deterioration and new tumor growth after one or two courses. The 13th patient had prolonged grade 2 thrombocytopenia after one course, and was taken off study when the lung metastases increased 62 days after treatment. L-AN at this dose and on this schedule had no detectable antitumor activity in patients with doxorubicin-resistant metastatic breast cancer.
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PMID:Phase II study of liposomal annamycin in the treatment of doxorubicin-resistant breast cancer. 1211 Nov 5

The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment.
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PMID:Taxanes, microtubules and chemoresistant breast cancer. 1806 31