Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A clinical phase I-II evaluation of 2-amino-1,3,4-thiadiazole (A-TDA) administered daily, twice a week, or weekly was undertaken, in which 71 patients were treated with a range of doses from 2 mg/m2 to 200 mg/m2. Pharmacokinetic studies employing high-performance liquid chromatography (HPLC) demonstrated a terminal (beta) serum half-life of 2.19 h. Stomatitis, dermatitis, nausea, vomiting, and lethargy were observed. No significant leukopenia or thrombocytopenia, however, was noted. A-TDA administration led to hyperuricemia, which was adequately controlled with concurrent administration of allopurinol. Antitumor responses included one partial response in a patient with large cell carcinoma of the lung and three objective responses (2 non-small cell lung and 1 squamous cell carcinoma of the esophagus). Two patients with adenocarcinoma of the lung had a marked improvement of psoriasis during A-TDA therapy. Further phase II studies in patients with cancer and trials in patients with psoriasis are recommended.
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PMID:Clinical and clinical pharmacologic studies of 2-amino-1,3,4-thiadiazole (A-TDA:NSC 4728). 293 41

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-nucleoside with antitumor activity against several murine tumor models, including Lewis lung carcinoma. The mechanism whereby this compound exerts its antineoplastic effects is most likely related to a state of guanine nucleotide depletion whereby the anabolite, thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of Tiazofurin administered on a 5-day, every-28-day schedule. Tiazofurin levels were measured using a high-pressure liquid chromatography assay, and pharmacokinetic studies were performed in patients treated at each dose level. Nineteen patients received a total of 24 courses of the drug in doses ranging from 550 to 2200 mg/sq m. The dose-limiting toxicities were pleuropericarditis and a general illness best described as a "viral-like" syndrome (manifested by severe malaise, headaches, myalgias, fever, nausea, vomiting, and diarrhea). Other toxicity included myelosuppression, hyperuricemia, elevated serum creatine phosphokinase and serum glutamic oxaloacetic transaminase, conjunctivitis, mucositis, and desquamation of the palms of the hands. Plasma clearance of Tiazofurin followed a biexponential pattern with a harmonic mean terminal half-life of 7.6 h. The mean volume of distribution at steady state was 30 liters/sq m, and the mean plasma clearance was 3 liters/h/sq m. The total cumulative urinary excretion ranged from 15 to 49%. The maximally tolerated dose of Tiazofurin on a 5-day schedule was 1650 mg/sq m. The recommended dose for Phase II evaluations is 1100 mg/sq m for 5 days. However, exploration of other schedules which might allow administration of more Tiazofurin combined with biochemical studies including thiazole-4-carboxamide adenine dinucleotide measurements would be desirable.
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PMID:Phase I evaluation and pharmacokinetics of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193). 398 13

Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted. The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase. Tiazofurin is widely distributed after i.v. administration exhibiting a triphasic pattern of plasma decay, with a terminal half-life of 3-16 h in the three species studied. Approximately 90% of the drug was excreted unchanged in the urine within 24 h. A significant potential for the slower release of intracellularly retained drug exists. Anticipated organ toxicities based on the studies described include myelotoxicity, hepatotoxicity and nephrotoxicity. These were mild and reversible at lower doses, and were not seen at levels corresponding to the starting doses in man. A potential for hyperuricemia exists; this should be easily controllable by the use of allopurinol, without compromising the drug's antitumor effect. Phase I trials under the sponsorship of the NCI are underway in a number of institutions.
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PMID:Tiazofurin: a new antitumor agent. 638 81