Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phase II study was undertaken to determine the efficacy of tirapazamine combined with cisplatin in patients with metastatic melanoma between April 1996 and April 1997. Tirapazamine 390 mg/m2, administered i.v. over 2 h, followed in 1 h by cisplatin 75 mg/m2 over 1 h, were used every 21 days to treat chemotherapy-naive patients with metastatic melanoma. Objective tumor measurements were used to assess efficacy of the regimen. NCI common toxicity criteria were used to grade toxicities. Forty-eight patients with metastatic melanoma of cutaneous or mucosal origin, none with symptomatic brain metastasis, were treated. Nine patients had a partial response, with an overall response rate of 20% (95% confidence interval: 9-33%). The median duration of response was 6 months. Grade 3 nausea, vomiting, anorexia, muscle cramps and fatigue occurred in fewer than 10% of patients. Neutropenia and thrombocytopenia were rare. This outpatient single-day administered tirapazamine-cisplatin regimen has definite activity in chemotherapy-naive patients with metastatic melanoma. Further studies in combination with other agents active against this disease are warranted.
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PMID:Phase II trial of escalated dose of tirapazamine combined with cisplatin in advanced malignant melanoma. 1057 6

Tirapazamine (TPZ) is a bioreductive drug that exhibits a high degree of selective toxicity toward hypoxic cells, and at doses that are used clinically, little or no cell killing is observed in aerobic cells. Nonetheless, the effects of TPZ on aerobic tissues are still responsible for the dose limitations on the clinical administration of this drug. Clinical side effects include fatigue, muscle cramping, and reversible ototoxicity. We have investigated TPZ-induced changes in the mitochondria in aerobically exposed cells as a potential mediator of these side effects. Our data show that aerobic administration of TPZ at clinically relevant doses results in a profound loss in the mitochondrial membrane potential (MMP). We show that loss in the MMP occurs in a variety of cell lines in vitro and also occurs in muscle tissues in vivo. The loss in MMP is temporary because recovery occurs within 2 h. TPZ is directly metabolized within mitochondria to a DNA-damaging form, and this metabolism leads to both the cell-killing effects of TPZ on aerobic cells at high doses and to the loss in MMP at clinically relevant doses. Using cell lines derived from genetically modified mice with a targeted deletion in manganese superoxide dismutase, we have further distinguished the phenotypic effects of TPZ in mitochondria at high toxic doses versus those at clinically relevant doses. We have investigated several potential mechanisms for this TPZ-induced loss in MMP. Our results indicate no change in the rate of cellular respiration in TPZ-treated cells. This implies that the loss in MMP results from an inability of the inner mitochondrial membrane to sustain a potential across the membrane after TPZ treatment. Incubation of cells with an inhibitor of the mitochondrial permeability transition suggests that the loss of MMP may result from the regulated opening of a large mitochondria channel.
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PMID:Mitochondrial dysfunction after aerobic exposure to the hypoxic cytotoxin tirapazamine. 1119 53

Our objective was to determine the maximum tolerated doses of tirapazamine and cyclophosphamide given i.v. in combination. Eligible patients had advanced solid tumors refractory to conventional treatment. Tirapazamine (escalated from 80 to 390 mg/m(2)) was given i.v. over 2 h and followed by cyclophosphamide over 1 h. The cyclophosphamide dose was fixed at 1000 mg/m(2) until the tirapazamine dose of 390 mg/m(2) was reached. Once that dose of tirapazamine was reached, the cyclophosphamide dose was escalated to 1250 and 1500 mg/m(2). Twenty-eight patients were enrolled. The dose-limiting toxicity was granulocytopenia. One patient had transient deafness for 2 days. Four other patients had grade 1 ototoxicity. Grade 1 and 2 muscle cramps were observed at all dose levels. Other toxic effects observed included fatigue, nausea, vomiting, headache, diarrhea, drug fever, elevated transaminases and elevated creatine phosphokinase. Three patients had stable disease and the longest time to progression was 5 months. The combination of tirapazamine and cyclophosphamide is feasible, and the dose-limiting toxicity is granulocytopenia. The use of growth factors could possibly allow escalation of tirapazamine doses in future phase II trials. Without growth factor support, the recommended doses of tirapazamine and cyclophosphamide when administered in this schedule are 260 and 1000 mg/m(2), respectively.
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PMID:Phase I trial of i.v. administered tirapazamine plus cyclophosphamide. 1145 95