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)

The accumulation of malignant ascites is a significant cause of morbidity and mortality in patients with intraabdominal malignancies. However, the cause of malignant ascites is unknown. In this study, we used the rat cremaster muscle preparation to determine if and how malignant ascites could produce protein leakage from normal blood vessels which would lead to fluid accumulation in the peritoneal cavity. The rat cremaster muscle, with nerves and blood vessels to the animal intact, was prepared for microscopic observations of the microcirculation. Serum albumin was tagged to fluorescein isothiocyanate and injected into the rat. Fluorescent microscopy was used to quantitate leakage of the tagged albumin into the interstitial tissue. Malignant ascites was collected from a patient with metastatic breast cancer. The ascites fluid was placed on the cremaster muscle and it induced protein leakage from the normal blood vessels of this tissue. Protein leakage was partially blocked by diphenhydramine (10(-4) M) and by mast cell depletion with compound 48/80. There was a high level of C3a in the malignant ascites solution but C3a did not increase during the exposure period. These data suggest that activated complement in malignant ascites may release histamine from mast cells to cause protein leakage of the normal vasculature. The movement of protein into the peritoneal cavity would be followed by water, thus increasing the volume of the ascites and exacerbating the clinical condition.
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PMID:Human malignant ascites and histamine-induced protein leakage from the normal microcirculation. 325 8

Aromatase activity was measured in 104 primary and 24 metastatic breast cancer patients. The assay employed quantitates the production of 3H water release from 1 beta-[3H]androstenedione after aromatization. Of 104 human primary breast tumors studied, 64 contained measurable aromatase activity, ranging from 5-70.5 pmol estrone formed/g protein/hour. In primary breast cancers there was no difference in levels of aromatase activity when analyzed by menstrual status or age by decade. Aromatase activity was similar in small and large primary tumors. The median aromatase activity of primary breast tumors (8.6 pmol/g/h) was similar to that found in metastatic breast cancer deposits (12.0 pmol/g/h). Aromatase activity did not correlate with either estrogen (ER) or progesterone (PR) receptor concentration in the tissues assayed. In this regard there were 33 ER- PR- tumor biopsies. Twelve of these 33 tumors contained aromatase activity greater than 10 pmol/g/hour.
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PMID:Aromatase activity in primary and metastatic human breast cancer. 380 35

We have used a highly sensitive high-performance liquid chromatographic assay to evaluate the pharmacokinetics and tissue disposition of mitoxantrone, an investigational anthracene derivative which has shown significant activity during Phase II clinical trials in the treatment of metastatic breast cancer, unfavorable histology non-Hodgkin's lymphoma, and acute leukemia. Mitoxantrone (12 mg/sq m over 30 to 35 min in 250 ml of dextrose 5% in water) and 14C-labeled mitoxantrone (specific activity, 8.85 muCi/mg) were administered to eight patients who had advanced soft tissue cancers. The plasma disappearance of mitoxantrone concentrations measured by high-performance liquid chromatography was best described by a three-compartment model with a mean t alpha of 0.1 h, a t beta of 1.1 h, and a t gamma of 42.6 h. The mean apparent Vc was 12.2 liters/sq m, while the mean Vd was 1875 liters/sq m. The mean plasma clearance was 0.57 liters/min/sq m, and the mean renal clearance was 45 ml/min/sq m. Only 6.5% of the total mitoxantrone dose was excreted in the urine as unchanged drug over 5 days. The mean recovery of 14C-labeled material in feces over 5 days was 18.3% of the administered dose. Thirty-five days after mitoxantrone administration to a patient who died of progressive kidney cancer, approximately 15% of the 14C dose could be accounted for in seven major organs. We conclude that mitoxantrone appears to distribute into a deep tissue compartment from which it is slowly released. These data provide a pharmacological rationale for use of mitoxantrone on an intermittent dosing schedule.
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PMID:Disposition of mitoxantrone in cancer patients. 397 48

The synthetic non-steroidal antioestrogen nafoxidine (U-11, 100A) was given by mouth to 52 women with locally advanced or metastatic breast cancer, in 85% of whom the disease had become resistant to, or relapsed after, previous endocrine treatment. The objective response rate (complete or partial regression of disease) among 48 cases treated for at least four weeks was 37%. Tumours in soft tissue seemed to respond better than skeletal metastases. The patients in all but one of the 52 cases were postmenopausal. Those who had had an objective response to previous hormone treatment had a greater chance of deriving benefit from nafoxidine than those who had been resistant to hormone treatment.Side effects of nafoxidine were dryness of skin, increased loss of scalp hair, and heightened sensitivity to sunlight. None were serious, and they could be lessened by protection from solar radiation or a decrease in dosage. No obvious depression of thyroid or adrenal function or obvious water retention or masculinization was seen. Cataract was a possible complication.This clinical trial was preceded by laboratory studies in which a transplantable oestrogen-dependent tumour in the Syrian hamster was notably inhibited by the administration of nafoxidine. This experimental model may prove useful in screening potentially useful antioestrogenic agents against breast cancer before a human trial.
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PMID:Antioestrogens in treatment of breast cancer: value of nafoxidine in 52 advanced cases. 436 55

CI-973 is a water-soluble platinum diamine complex whose antitumor activity is greater than that of cisplatin in some murine tumors. It has shown activity against cisplatin-resistant tumors. This phase II trial had the objectives of determining the therapeutic efficacy of CI-973 in patients with metastatic breast cancer who had been treated with one prior chemotherapy regimen, and of further defining the toxicity of the agent and the reversibility of its toxicity. CI-973 was administered as an intravenous infusion over 30 min with no prehydration or antiemetic programs. Treatment cycles were repeated at 21-day intervals. Patients with histologically confirmed metastatic breast cancer, measurable disease, and good performance status who had received only one prior chemotherapy regimen for metastatic disease were eligible for treatment. Adequate hematologic, renal, and hepatic function were required. A total of 26 patients received a median of two courses of CI-973 (range, 1-18 courses). Hematologic toxicity was severe: nearly all patients experienced granulocytopenia with granulocyte counts of 0 at all dose levels. Nevertheless, neutropenic fever and documented systemic infection were uncommon, and there were no hospitalizations for neutropenic fever or infection. Visceral disease dominated in this patient group. Of the 26 patients, 14 had visceral disease, 6 had bone or bone marrow disease, and 6 had skin, soft-tissue, or lymph-node disease. Of the 26 patients treated, 25 were evaluable for response. There were two partial remissions, one in liver and one in bone, and three minor responses, for a response rate of 8%. Nonhematologic toxic effects were mild and consisted of nausea and vomiting, fatigue, minimum peripheral paresthesia, and hypomagnesemia. Further study of CI-973 at the dose and schedule used in this study is not warranted. Because this agent had no significant extramedullary toxicity, intensification of the dose of CI-973 with concomitant administration of colony-stimulating factors has the potential to improve response in this patient population.
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PMID:A phase II study of CI-973 [SP-4-3(R)]-1,1-cyclobutane-dicarboxylato (2-)] (2-methyl-1,4-butanediamine-N, N') platinum in patients with refractory advanced breast cancer. 864 5

9-Amino-20(S)-camptothecin (9-AC) is an analog of camptothecin with limited water solubility which has shown significant preclinical activity in a variety of human solid tumor xenografts. A Phase I trial using a soluble formulation of 9-AC, given as a 72-hour continuous infusion, has been completed. Thirty-one patients with resistant cancers received 5-60 micrograms/M2/h at three week intervals. The Maximum Tolerated Dose (MTD) was 45 micrograms/M2/hour. Neutropenia was the dose limiting toxicity, with few significant non-myelosuppressive toxicities. Minor responses were seen in 3/31 patients. Pharmacokinetic studies of 9-AC lactone (closed ring) showed substantial interpatient variability with a predicted half-life of 36 hours. A phase I/II trial of the same formulation of 9-AC is ongoing in refractory leukemia. Stomatitis and diarrhea are the non-myelosuppressive dose limiting toxicities. Evidence of antineoplastic activity has been seen in 3/15 patients. A Phase II trial in previously untreated metastatic breast cancer is also underway. A Phase I trial of a colloidal dispersion formulation, not yet completed, is better tolerated with a MTD > 45 micrograms/M2/h as a 72-hour continuous infusion. Evidence of antineoplastic activity has also been demonstrated.
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PMID:Trials of 9-amino-20(S)-camptothecin in Boston. 899 18

A number of recent preclinical studies have sparked interest in the concept of exploiting conventional chemotherapeutic drugs as antiangiogenics. Such antiangiogenic activity is achieved or optimized by metronomic-dosing protocols in which the drug is given at comparatively low doses using a frequent schedule of administration (e.g., once to three times per week) with no breaks, particularly when combined with an endothelial cell-specific antiangiogenic drug. The use of p.o. chemotherapeutic drugs is particularly suitable for this type of treatment strategy. We tested one such drug, cyclophosphamide (CTX), in a protocol wherein the drug was administered to mice at low doses, of approximately 10-40 mg/kg on a daily basis through the drinking water. CTX is typically given p.o. to patients, but it has almost always been injected when treating preclinical mouse tumor models. We found p.o. CTX to be a safe and convenient treatment with significant antitumor efficacy. Growth delays were observed for human orthotopic breast or ectopic colon cancer xenografts in nude or SCID mice. Established PC3 human prostate tumor xenografts could be induced to almost fully regress, remaining virtually nonpalpable for > or =2 months of continuous therapy, after which tumors began to grow progressively. These re-emergent tumors were not found to be drug resistant when tested in new hosts, using the same treatment protocol. Regression of spontaneously arising, late-stage pancreatic islet cell carcinomas in Rip Tag transgenic mice was also observed. The effects of continuous p.o. CTX treatment were enhanced significantly in an orthotopic, metastatic breast cancer xenograft model when used in combination with an antivascular endothelial growth factor receptor-2 blocking antibody. Maximum tolerated dose levels established for other mouse strains proved highly toxic to SCID mice, whereas daily p.o. low-dose regimens of CTX were well tolerated. Taken together, the results demonstrate the feasibility of delivering CTX in a p.o. metronomic chemotherapy regimen, which proved safe, reasonably efficacious, and potentially applicable to chronic treatment. Such a regimen may be particularly well suited for integration with antiangiogenic drugs.
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PMID:Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. 1201 44

The goal of oncology is the individualization of patient care to optimize therapeutic responses and minimize toxicities. Achieving this will require noninvasive, quantifiable, and early markers of tumor response. Preclinical data from xenografted tumors using a variety of antitumor therapies have shown that magnetic resonance imaging (MRI)-measured mobility of tissue water (apparent diffusion coefficient of water, or ADCw) is a biomarker presaging cell death in the tumor. This communication tests the hypothesis that changes in water mobility will quantitatively presage tumor responses in patients with metastatic liver lesions from breast cancer. A total of 13 patients with metastatic breast cancer and 60 measurable liver lesions were monitored by diffusion MRI after initiation of new courses of chemotherapy. MR images were obtained prior to, and at 4, 11, and 39 days following the initiation of therapy for determination of volumes and ADCw values. The data indicate that diffusion MRI can predict response by 4 or 11 days after commencement of therapy, depending on the analytic method. The highest concordance was observed in tumor lesions that were less than 8 cm3 in volume at presentation. These results suggest that diffusion MRI can be useful to predict the response of liver metastases to effective chemotherapy.
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PMID:Changes in water mobility measured by diffusion MRI predict response of metastatic breast cancer to chemotherapy. 1572 Aug 10

Paclitaxel is an anticancer agent effective for the treatment of breast, ovarian, lung, and head and neck cancer. Because of water insolubility, paclitaxel is formulated with the micelle-forming vehicle Cremophor EL to enhance drug solubility. However, the addition of Cremophor EL results in hypersensitivity reactions, neurotoxicity, and altered pharmacokinetics of paclitaxel. To circumvent these unfavorable effects resulting from the addition of Cremophor EL, efforts have been made to develop new delivery systems for paclitaxel administration. For example, ABI-007 is a Cremophor-free, albumin-stabilized, nanoparticle paclitaxel formulation that was found to have significantly less toxicity than Cremophor-containing paclitaxel in mice. Pharmacokinetic studies indicate that in contrast to Cremophor-containing paclitaxel, ABI-007 displays linear pharmacokinetics over the clinically relevant dose range of 135-300 mg/m(2). In a phase III study conducted in patients with metastatic breast cancer, patients treated with ABI-007 achieved a significantly higher objective response rate and time to progression than those treated with Cremophor-containing paclitaxel. Together these findings suggest that nanoparticle albumin-bound paclitaxel may enable clinicians to administer paclitaxel at higher doses with less toxicity than is seen with Cremophor-containing paclitaxel. The role of this novel paclitaxel formulation in combination therapy with other antineoplastic agents needs to be determined.
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PMID:Paclitaxel chemotherapy: from empiricism to a mechanism-based formulation strategy. 1836 May 50

Solvent-based delivery vehicles for chemotherapy agents have been instrumental in providing a means for hydrophobic agents to be administered intravenously. These solvents, however, have been associated with serious and dose-limiting toxicities. Solvent-based formulations of taxanes, a highly active class of cytotoxic agents, are associated with hypersensitivity reactions, neutropenia, and neuropathy. Nanoparticle technology utilizing the human protein albumin exploits natural pathways to selectively deliver larger amounts of drug to tumors while avoiding some of the toxicities of solvent-based formulations. 130 nM albumin-bound (nab) paclitaxel (nab-paclitaxel; Abraxane) was recently approved for use in patients with metastatic breast cancer who have failed combination therapy. In a randomized, phase III study in metastatic breast cancer, nab-paclitaxel was found to have improved efficacy and safety compared with conventional, solvent-based paclitaxel. Preliminary data also suggest roles for nab-paclitaxel as a single agent and in combination therapy for first-line treatment of metastatic breast cancer as well as in other solid tumors, including non-small-cell lung cancer, ovarian cancer, and malignant melanoma. The nab technology promises to have broad utility in cancer therapy, and clinical trials are underway using nab formulations of other water-insoluble anticancer agents such as docetaxel and rapamycin.
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PMID:Protein nanoparticles as drug carriers in clinical medicine. 1842 79


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