Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxantrazole (now designated as piroxantrone) is an anthrapyrazole analog under evaluation as a potentially useful anthracycline-like antitumor agent. In preparation for phase I clinical trials, we characterized certain aspects of oxantrazole preclinical pharmacology, including plasma stability, murine pharmacokinetics, in vitro/in vivo metabolism, and DNA damage following incubation with human tumor cells in culture. Oxantrazole was relatively unstable in fresh mouse and dog plasma and particularly unstable in fresh human plasma (t 1/2 less than 5 min at 37 degrees C). Its decomposition in plasma was prevented by the addition of ascorbic acid, suggesting oxidative degradation. Following rapid i.v. administration of oxantrazole to mice, plasma elimination was best described by a two-compartment open model with an elimination-phase half-life, total body clearance, and steady-state volume of distribution of 330 min, 458 ml/min per m2, and 87.9 l/m2, respectively. The c x t value calculated following i.v. administration of 90 mg/m2 oxantrazole to mice was 177 micrograms-min/ml. This value was subsequently used in a pharmacologically guided dose-escalation scheme for the oxantrazole phase I clinical trial. Oxantrazole was converted to a polar conjugate, presumably a beta-glucuronide, by rat but not mouse hepatic microsomal preparations and in vivo by the mouse. Oxantrazole introduced protein-associated DNA strand breaks following incubation with a human rhabdomyosarcoma cell line. Repair of the damage was complete by 15 h. Clinical pharmacologic studies are currently under way in conjunction with the phase I clinical trial of oxantrazole.
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PMID:Preclinical pharmacology of the anthrapyrazole analog oxantrazole (NSC-349174, piroxantrone). 292 79

The preactivated cyclophosphamide analogue, 4-HC, does not require activation by hepatic microsomal enzymes to express its cytotoxic activity and therefore, unlike cyclophosphamide, may be useful for the regional therapy of cancer. In the present study, the pharmacokinetics and toxicology of 4-HC were studied following intraventricular administration of 0.4 mg to rhesus monkeys with chronic indwelling Ommaya reservoirs. 4-HC was measured in cerebrospinal fluid (CSF) and plasma with a high-performance liquid chromatography assay utilizing a fluorometric detector following derivatization with m-aminophenol. The mean peak level of 4-HC in ventricular CSF was 100 microM 5 min after administration. The drug was cleared rapidly and the elimination was monoexponential with a mean half-life of 22 min. The mean clearance from CSF (0.33 ml/min) was 10-fold higher than CSF bulk flow. The drug was distributed throughout the subarachnoid space with lumbar levels approaching ventricular levels by 60 min. Neither acute nor chronic neurotoxicity or systemic toxicity was observed during the 6-wk observation period. Concentrations of 4-HC demonstrated to be cytocidal in vitro against human breast cancer, lymphoid leukemia, and rhabdomyosarcoma were readily achieved in CSF following intraventricular administration. This study demonstrates that intraventricular therapy with 4-HC is feasible and suggests that further study of this approach in the clinical setting should be considered.
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PMID:Intrathecal administration of 4-hydroperoxycyclophosphamide in rhesus monkeys. 366 93

Tumour necrosis factor-alpha (TNF) receptors mediate a variety of effects dependent on cell type. A role for Ca2+ in TNF-induced death remains uncertain. Here we investigated restricting intracellular/extracellular Ca2+ in HeLa epithelial carcinoma cells expressing low and high levels of p75TNFR receptor subtype and KYM-1 rhabdomyosarcoma cells, models of rapid TNF-induced apoptosis. Ca2+ -chelators EGTA and BAPTA-AM as well as microsomal Ca2+ -ATPase inhibitor thapsigargin, did not alter TNF-induced death. TNF was also unable to alter resting [Ca2+]i levels which remained < 200 nM even during times when these cells were undergoing apoptotic cell death. These findings indicate no role for modulated Ca2+ concentrations in TNF-induced apoptotic cell death.
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PMID:Unmodified calcium concentrations in tumour necrosis factor receptor subtype-mediated apoptotic cell death. 1105 43