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)

Maytansine has significant antitumor activity in animal model systems. The initial clinical trial of maytansine was carried out in 38 adult solid tumor patients. Five daily bolus injections were repeated at 21-day intervals. A total of 78 courses were administered over a dose range of 0.1--0.8 mg/m2/day X 5 days. Gastrointestinal toxicity was dose-related and dose-limiting at doses of greater than or equal to 0.5 mg/m2. Dose-related neurotoxicity was also observed. No drug-related myelosuppression or change in serum creatinine level was seen. Hepatic toxicity was subclinical and reversible. Of 16 patients evaluable for response, two with breast cancer had therapeutic benefit. Phase II studies of maytansine are recommended at a starting dose of 2.0--2.5 mg/m2/course repeated at 21-day intervals.
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PMID:Maytansine: a phase I study of an ansa macrolide with antitumor activity. 34 12

During the phase I study of maytansine at our institution, some activity was observed against breast carcinoma and melanoma. A phase II study was thus initiated to more thoroughly investigate the activity of this drug against these two tumors. In 33 evaluable patients with melanoma, no complete or partial responses were observed. Twenty-one evaluable patients with breast cancer were entered and only one response (partial) was seen. The toxicity was similar to that observed in the phase I study and consisted mainly of diarrhea, paresthesias, phlebitis, and flu-like symptoms. Myelosuppression was infrequent and was short-lived when it occurred.
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PMID:Results of a phase II study of maytansine in patients with breast carcinoma and melanoma. 37 3

A mammary adenocarcinoma (16/C) was isolated and maintained in serial passage by transplantation of metastatic lung foci. This tumor originated as a spontaneous mammary adenocarcinoma in a C3H/He female mouse. It was selected as a model from greater than 50 mammary tumors studied because it was highly metastatic and because it responded to most of the agents reported to be active against breast cancer in women. Sc implanted 16/C tumors (in the 300--1000-mg range) metastasized to the lungs in greater than 75% of the mice and to the axillary lymph nodes in greater than 30%. This tumor has been tested for sensitivity to greater than 40 clinically used agents. Adriamycin was the most active single agent. Other active agents included cyclophosphamide, 5-fluorouracil, vincristine, melphalan, dibromodulcitol, maytansine, neocarzinostatin, palmO-ara-C, vinblastine, and VP-16-213. Agents most active against 40--1000-mg tumours were also most active against micrometastatic disease (eg, adriamycin). The converse was also true; agents inactive or marginally active against 40--1000-mg tumors were at best marginally active against micrometastatic disease (eg, BCNU). Tumors greater than 20 mg were not curable by chemotherapy alone, although adriamycin treatment caused complete regressions of 100--400-mg tumors in greater than 80% of the mice. Surgical removal of 300--1000-mg tumors plus therapy with adriamycin resulted in 40%--72% cures as compared to 0--26% cures with surgery only. Data resulting from treatment with other agents, singly and in combination, are presented.
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PMID:Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy. 70 50

Methotrexate (MTX) in high doses (3 to 7.5 g/m2) with leucovorin rescue (HDMTX-LCV) can be delivered on a weekly basis in a setting of proper pharmacologic monitoring. Myelosuppression occurs in 28 per cent of the patients and in 8 per cent of the courses and usually results from delayed MTX excretion secondary to mild reversible nephrotoxicity. The incidence of tumor regression was 50 per cent in head and neck cancer; 59 per cent in non-Hodgkin's lymphoma; 40 per cent in small cell lung cancer; 24 to 50 per cent in breast cancer and 50 per cent in osteogenic carcinoma, for an over-all response rate of 39 per cent (70 of 178) in patients with disseminated cancer. HDMTX-LCV is not recommended for the conventional treatment of metastatic cancer because of the potential for toxicity and the fact that the response rates cited are probably not superior to those which can be achieved by conventional doses of MTX. However, the relative lack of myelosuppression and mucositis, when compared to conventional unrescued MTS, and the achievement of therapeutic concentrations of MTX in the central nervous system with the HDMTX-LCV program have led to its incorporation into clinical trials of combination chemotherapy.
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PMID:High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity. 696 19

Maytansine is an experimental antitumor agent that has shown minimal efficacy against breast cancer with minimal myelosuppression in phase I trials. Forty-one patients with advanced drug-resistant breast cancer were treated with a 5-day intermittent iv infusion of maytansine repeated every 21 days. All patients had been heavily pretreated with cyclophosphamide, methotrexate, 5-fluorouracil, or doxorubicin, and 12 had received vinblastine, mitomycin C, or investigational drugs. All patients had measurable disease and an expected survival of 6 weeks. The average performance status was 2.5. Twelve patients did not complete one full cycle of therapy, leaving 29 evaluable for response. One patient had a partial regression of pulmonary disease, seven had transient responses of less than 50% reduction in tumor or stable disease, and 21 had progressive disease. Toxic effects (vomiting, diarrhea, ileus, lethargy, and altered mentation) were considerable. Since maytansine is a relatively nonmyelotoxic metaphase inhibitor, we feel that even minimal efficacy in heavily pretreated patients justifies further evaluation of the agent in combination therapy.
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PMID:Minimal single-agent activity of maytansine in refractory breast cancer: a Southwest Oncology Group study. 742 53

Breast cancer has a prodigious capacity to metastasize to bone. In women with advanced breast cancer and bone metastases, bisphosphonates reduce the incidence of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that some bisphosphonates reduce the tumour burden in bone with a consequent increase in survival, raising the possibility that bisphosphonates may have a direct effect on breast cancer cells. We have investigated the in vitro effects of bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth, viability and induction of apoptosis in three human breast cancer cell lines (MDA-MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye assay, and cell viability was quantitated by MTS dye reduction. Induction of apoptosis was determined by identification of morphological features of apoptosis using time-lapse videomicroscopy, identifying morphological changes in nucleis using Hoechst staining, quantitation of DNA fragmentation, level of expression of bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly (ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced cell viability in all three cell lines. Zoledronate was the most potent bisphosphonate with IC50 values of 15, 20 and 3 microM respectively in MDA-MB-231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35 and 25 microM, whereas clodronate and EB 1053 were more than two orders of magnitude less potent. An increase in the proportion of cells having morphological features characteristic of apoptosis, characteristic apoptotic changes in the nucleus, time-dependent increase in the percentage of fragmented chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of PARP, all indicate that bisphosphonates have direct anti-tumour effects on human breast cancer cells.
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PMID:Bisphosphonates induce apoptosis in human breast cancer cell lines. 1078 May 27

Although docetaxel (Taxotere; TXT), a taxoid anticancer drug, is clinically and experimentally very effective against breast cancer, its antitumor effect is of very short duration. We addressed whether 5-fluorouracil (5-FU) and its derivatives can act synergistically with TXT against mammary tumors, with placing particular stress on their use by oral route. Mouse mammary tumor cell line, MM2, was propagated in culture and as ascites in mice. Carmofur (HCFU) and doxifluridine (5'-DFUR) were used as 5-FU derivatives. In vitro, the cytotoxic effects of antitumor drugs on MM2 cells were examined by MTS assay. In vivo, mice inoculated i.p. with MM2 cells were treated with i.p. injection of TXT and/or oral administration of 5-FU or its derivatives, and observed for curing tumor. In vitro, the synergistic effects were observed in the combination of TXT and 5-FU or HCFU, but not in that of TXT and 5'-DFUR. In vivo, all of these combinations cured tumors far more effectively than TXT alone. The discrepant result of the combination of TXT and 5'-DFUR between in vitro and in vivo was ascribed to up-regulation of pyrimidine phosphorylase in tumor cells in vivo by TXT. Thus, 5-FU, its masked compounds like HCFU and its prodrugs like 5'-DFUR can act synergistically with TXT in the therapy of cancer even when administered by the oral route.
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PMID:Docetaxel alone or orally combined with 5-fluorouracil and its derivatives: effects on mouse mammary tumor cell line MM2 in vitro and in vivo. 1160 57

Thymidylate synthase (TS) is responsible for the de novo synthesis of thymidylate, which is required for DNA synthesis and repair and which is an important target for fluoropyrimidines such as 5-fluorouracil (5-FU), and antifolates such as Tomudex (TDX), ZD9331, and multitargeted antifolate (MTA). To study the importance of TS expression in determining resistance to these agents, we have developed an MDA435 breast cancer-derived cell line with tetracycline-regulated expression of TS termed MTS-5. We have demonstrated that inducible expression of TS increased the IC(50) dose of the TS-targeted therapeutic agents 5-FU, TDX, and ZD9331 by 2-, 9- and 24-fold respectively. An IC(50) dose for MTA was unobtainable when TS was overexpressed in these cells, which indicated that MTA toxicity is highly sensitive to increased TS expression levels. The growth inhibitory effects of the chemotherapeutic agents CPT-11, cisplatin, oxaliplatin, and Taxol were unaffected by TS up-regulation. Cell cycle analyses revealed that IC(50) doses of 5-FU, TDX and MTA caused an S-phase arrest in cells that did not overexpress TS, and this arrest was overcome when TS was up-regulated. Furthermore, the S-phase arrest was accompanied by 2- to 4-fold increased expression of the cell cycle regulatory genes cyclin E, cyclin A, and cyclin dependent kinase 2 (cdk2). These results indicate that acute increases in TS expression levels play a key role in determining cellular sensitivity to TS-directed chemotherapeutic drugs by modulating the degree of S-phase arrest caused by these agents. Moreover, CPT-11, cisplatin, oxaliplatin, and Taxol remain highly cytotoxic in cells that overexpress TS.
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PMID:Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS- and non-TS-targeted chemotherapies. 1170 73

Breast cancer is a rare, but frequently hidden pathology. A woman, 36 years old, during the early months of pregnancy found a little tumor in her right breast. A fine needle biopsy was negative for cancer. Despite this, the tumor rose and two months after delivery (the patient breast-fed her daughter for a month), she had pain in the right axillary region and the tumors involved all superior dials of the right breast. A Madden mastectomy was performed. The histopathological report was: ductal invasive breast cancer 3 of 19 lymph nodes involved, stage IIIA, TNM pT3N2M0, ER -, PgR +--. Chemotherapeutic regimens were: at first ADM 75 mg/m2 for 5 cycles, and after CMF 1-8 for 6 cycles. After six months the woman had a cutaneous recurrence in the scar of mastectomy, treated with surgery and RT. Thirteen months after, she had lung MTS and then brain MTS. The patient died thirty months after the mastectomy. The surgeons have to discover the women high-risk for the breast cancer before and during the pregnancy. Excisional biopsy is the diagnostic procedure of choice for breast lump during pregnancy. When a breast cancer develops during a pregnancy, the surgeon has to operate immediately the tumors. Chemotherapeutic regimens should be delayed until the second o third trimester or after delivery.
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PMID:[Breast carcinoma in pregnancy: a clinical case]. 1240

Exemestane, a non-steroidal aromatase inhibitor that shuts down estrogen synthesis, and paclitaxel, an antineoplastic drug, inhibiting microtubule formation and interfering with the cells potential to proliferate, are well established treatments for metastatic breast cancer. Given that exemestane is a treatment for hormone-sensitive tumors in postmenopausal women with more favorable prognosis, while paclitaxel is normally used for women suffering from hormone-insensitive breast cancers with less favorable prognoses, there is currently no experience with the combination of the two drugs. In order to find out to what extent exemestane and paclitaxel add to each other's effects when given concomitantly, the effect of the two drugs alone and in combination on the growth of various gynecological tumor cell lines was assessed. Tumor cell growth was measured according to the cell titer cell proliferation technique, also referred to as the MTS assay, by measurement of relative cell numbers. In gynecological cancer cells expressing aromatase, the effect of a treatment with paclitaxel (10 nM) on cell growth was enhanced by co-treatment with exemestane. This additive effect was independent of ERalpha expression, but dependent on the presence of androstenedione. It was observed in HEC-1A and Ishikawa endometrial adenocarcinoma cells as well as in SK-OV-3 ovarian cancer and in MDA-MB-231 breast cancer cells. Our findings suggest that a combination of paclitaxel with exemestane might be beneficial for the treatment of aromatase-positive gynecological cancer, because it may allow us to reduce the paclitaxel dosage and therefore the toxicity of the treatment.
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PMID:Effects of a combination of exemestane and paclitaxel on human tumor cells in vitro. 1509 Jul 44


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