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)

Both alpha-difluoromethyl ornithine (DFMO) and methylglyoxal bis (guanylhydrazone) (MGBG) inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells and DFMO combined with MGBG has shown synergistic cytotoxicity in an experimental prostatic tumor, we evaluated these agents in phase I clinical trial involving 5 patients with advanced, hormone-resistant prostatic cancer. Toxic reaction to combined DFMO and MGBG was dose-related and included nausea, fatigue, and diarrhea especially with the higher doses of MGBG. No therapeutic responses of significance were seen, but toxicity precluded adequate evaluation. Future Phase II studies of combined DFMO and MGBG should employ low, nontoxic doses of MGBG combined with evaluation of polyamine levels and inhibition of polyamine enzymatic activity to minimize toxicity.
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PMID:Phase I trial of alpha-difluoromethyl ornithine (DFMO) and methylglyoxal bis (guanylhydrazone) (MGBG) in patients with advanced prostatic cancer. 309 3

Fifty-two patients with metastatic or recurrent non-small-cell lung cancer (NSCLC) were treated, during a phase II trial, with methylglyoxal-bis-(guanylhydrazone) (MGBG). Of the 44 patients who had adequate trials, 4 had partial responses (PR), for an overall 9% PR rate. Response durations ranged from 3 to 5+ months. Prior treatment with chemotherapy may have adversely affected response rate; 15% of previously untreated patients responded, compared to only 4% of previously treated patients. A syndrome of weakness and fatigue was the most serious side effect. Anorexia and weight loss, stomatitis, nausea and vomiting, diarrhea, and peripheral neuropathy were the other toxic effects. We conclude that MGBG has activity in NSCLC, especially in previously untreated patients, and further studies are indicated in that population.
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PMID:Phase II trial of methylglyoxal-bis-(guanylhydrazone) in non-small-cell lung cancer. 627 32

Thirty-nine patients received 600 mg/m2 OF MGBG intravenously every week for the treatment of advanced refractory ovarian cancer. Twenty-seven of these received adequate trials, and only two had partial remissions lasting 3 1/2 and 4 months each. Toxicity was substantial, with severe hematologic toxicity in 26%, diarrhea in 22% (severe in 7%), skin rash in 26% (severe in 7%), and vomiting in 70% (severe in 11%). Fatigue, facial paresthesias, and flushing during drug administration were frequent. It appears that MGBG in this dose and schedule has little activity against advanced ovarian cancer.
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PMID:Phase II study of methyl-glyoxal bis-guanylhydrazone (NSC 3296) in advanced ovarian cancer. 652 67

Broad phase II trial of methylglyoxal-bi (guanylhydrazone) (MGBG) is under way at the Memorial Sloan-Kettering Cancer Center. Studies in renal cell carcinoma, lymphomas, and non-small-cell lung cancer are completed, and substantial numbers of patients with esophageal and head and neck cancer have been treated. Small numbers of patients with other solid tumors have also been entered into the study. MGBG has significant antineoplastic activity against lymphomas, with 16/40 heavily pretreated patients (40%) having partial remissions (PR) lasting 1 to 8+ months. MGBG has also demonstrated more modest activity in non-small-cell lung cancer, esophageal, and head and neck carcinoma; it appears to have little or no therapeutic value in renal cell cancer. Toxicities have been manageable, and included mild nausea and vomiting, diarrhea, mucositis, and myelosuppression. The dose-limiting toxicity, seen most frequently in those patients with impaired renal function, was lethargy and fatigue. MGBG has demonstrated activity in lymphomas, lung, esophageal, and head and neck cancer. Further trials of this agent are indicated, both alone and in combination.
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PMID:Phase II trials of methylglyoxal-bis (guanylhydrazone). 704 14

Medaka, Oryzias latipes, were exposed in ovo to the polyamine (PA) biosynthesis inhibitors alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) (MGBG). In an additional group, spermine, the end product of the PA pathway, was added with DFMO and MGBG for a "rescue" treatment. At 4 days posthatch, length, DNA and RNA content, and swimming endurance were measured. The only parameter affected by treatment was swimming endurance which revealed decreased latent time to fatigue with increased dose, although not statistically significant. The rescue group, however, did demonstrate a statistically significant decrease in fatigue latency as compared to controls.
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PMID:Early life-stage effects in medaka (Oryzias latipes) following in ovo exposure to polyamine biosynthetic inhibitors. 752 27

Because tumour cell proliferation is highly dependent upon up-regulation of de-novo polyamine synthesis, inhibition of the polyamine synthesis pathway represents a potential target for anticancer therapy. SAM486A (CGP 48664) is a new inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), more potent and specific than the first-generation SAMDC inhibitor methylglyoxal (bis) guanylhydrazone (MGBG). Preclinical testing confirmed promising antiproliferative activity. In this phase I study, SAM486A was given 4-weekly as a 120 h infusion. 39 adult cancer patients were enrolled with advanced/refractory disease not amenable to established treatments, PS </= 2, adequate marrow, liver, renal and cardiac function. Doses were escalated in 100% increments without toxicity in 24 pts from 3 mg m(-2)cycle(-1)up to 400 mg m(-2)cycle(-1). At 550 and 700 mg m(-2)cycle(-1)reversible dose-limiting neutropenia occurred. Other toxicities included mild fatigue, nausea and vomiting. No objective remission was seen. Pharmakokinetic analysis showed a terminal half-life of approximately 2 days. AUC and Cmax were related to dose; neutropenia correlated with AUC. The recommended dose for further phase II studies on this schedule is 400 mg m(-2)cycle(-1).
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PMID:A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours. 1094 98