Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavone acetic acid represents a novel chemical structure currently undergoing clinical investigation. Broad spectrum activity has been observed in preclinical animal screens, but at doses close to toxic in mice. Phase I clinical trials have established that equivalent plasma drug levels can be achieved in humans, but to date Phase II trials have not demonstrated significant activity in a range of tumor types. Little is known about the drug's biotransformation, although metabolites have been implicated in proposed mechanisms of action. In this paper, we have purified the two major human metabolites present in urine (also the only two metabolites detected in plasma) and characterized their structure, chemical properties, activity, and pharmacokinetics. Metabolite 1 (M1) was a glucuronide conjugated to the 8-acetic acid grouping (Mr 456), was chemically labile, and showed a strong tendency to undergo chemical rearrangement at mildly alkaline pH. Metabolite 2 (M2) was also a glucuronide (Mr 456) but appeared to be an unusual isomer of M1. Both were noncytotoxic. In patients, biotransformation represented the predominant mechanism of drug clearance with as much as 80% of a low dose (0.5 g/m2) recovered in urine as M1 and M2 after only 6 h. At high dose (4.8 to 8.6 g/m2, 1- to 6-h infusion) the appearance of peak concentrations of metabolites in plasma and urine was delayed, apparently due to saturation of glucuronidation pathways. This resulted in an overall reduction in drug clearance by 3- to 4-fold. Mice cleared flavone acetic acid much more slowly than patients (289 ml/h/m2 after 600 mg/m2 i.p. versus 2.3 liters/h/m2 after 4.8 g/m2-1-h i.v. infusion) without producing M1 or M2. A different metabolite, exhibiting characteristics of a conjugate, was detected at low concentrations in plasma, tissues, and tumor. Extensive metabolism to inactive products followed by their rapid clearance may contribute to the lack of activity so far seen in humans.
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PMID:Characterization of the major metabolites of flavone acetic acid and comparison of their disposition in humans and mice. 273 Nov 78

Some investigators have suggested that the marked activity of flavone acetic acid (FAA) against advanced solid tumors in mice results from an indirect effect. This study indicates that the critical effect of FAA is irreversible inhibition of tumor blood flow. Perfusion of sc Colon 38 tumors, assessed with H33342 as a fluorescent stain for functional blood vessels, was reduced to 50% of controls within 3 hours of an ip injection of 1.2 mmol of FAA/kg and was completely inhibited by 24 hours. A double-label fluorescence technique demonstrated a significant decrease in blood flow in both sc Colon 38 and im EMT-6/Ak tumors as early as 15 minutes after iv treatment with 1.2 mmol of FAA/kg, with progressively enlarging zones of perfusion failure. The rate of cell death in totally ischemic EMT-6 tumors was shown to be sufficiently rapid to represent a major component of the observed antitumor effect of FAA if the flavonoid acts via inhibition of blood flow. Further, avascular EMT-6/Ak multicellular spheroids growing in the mouse peritoneum are relatively resistant to killing by FAA administered iv or ip, despite extensive infiltration with host immune cells. These results indicate that inhibition of tumor blood flow by FAA is a necessary component of its antitumor activity against solid tumors.
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PMID:Blood flow failure as a major determinant in the antitumor action of flavone acetic acid. 273 44

Gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) is a chelated paramagnetic contrast agent under clinical trial for use in magnetic resonance (MR) imaging. The increased signal intensity following the intravenous infusion of contrast medium may improve the ability of MR imaging to delineate tumors. The use of this method in 15 pediatric patients with suspected brain-tumor recurrence was analyzed. All 15 patients underwent postoperative Gd-DTPA-enhanced MR imaging, and residual tumor was demonstrated in nine of them. Based on the findings of the enhanced MR studies, four patients had additional surgery, two underwent radiation therapy, and one was given immunotherapy. Continued surveillance was recommended for the remaining eight patients. In all cases the enhanced MR imaging studies were superior to the unenhanced studies in regard to the qualitative and quantitative assessment of the residual tumor. Gadolinium-DTPA-enhanced MR imaging appears to be a safe and effective means of providing an accurate postoperative assessment of residual disease in pediatric brain-tumor patients. It is as effective as contrast-enhanced computerized tomography and has the sensitivity and anatomic resolution provided by MR imaging. The most useful role of this agent was in the postoperative period, in assessing the adequacy of surgical resection. This technique is recommended as the procedure of choice in the postoperative assessment and long-term surveillance of patients with brain tumors.
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PMID:Unenhanced and gadolinium-DTPA-enhanced MR imaging in postoperative evaluation in pediatric brain tumors. 273 40

Sixty pmoles of a material with molecular size, immunological, and RP-HPLC characteristics identical to that of h beta MSH(5-22) were purified from a bronchial carcinoid tumor responsible for the ectopic ACTH syndrome. The first 16 cycles of microsequencing revealed the following sequence: Asp-Glu-Gly-Pro-Tyr-Arg-Met-Glu-X-Phe-Arg-Trp-Gly-X-Pro- Pro-, identical to the first 16 amino acids of h beta MSH(5-22). Since this material was recognized by an antibody which requires the free COOH-terminal Asp22 residue, it can be assumed that it is indeed h beta MSH(5-22). We also show that neither the 5 N acetic acid nor the 1 N HCl extraction procedure artefactually generated h beta MSH-like material in normal or tumoral human pituitaries and in nonpituitary tumors. We conclude that h beta MSH(5-22) is a normal maturation product of proopiomelanocortin in the human nonpituitary tissues which express its gene, including the hypothalamus and ACTH-secreting tumors.
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PMID:Microsequencing evidence for the maturation of human proopiomelanocortin into an 18 amino acid beta-melanocyte stimulating hormone [h beta MSH(5-22)] in nonpituitary tissue. 274 27

Venereal warts are an ancient disease, but the relationship between certain human papillomavirus serotypes and genital neoplasia is just being recognized. Women are at higher risk for development of neoplasia from the infection and are more likely to be reinfected, because a male partner's lesions may be invisible without application of acetic acid or examination of a urethral smear. Other factors that favor progression to cancer are young age at first exposure, multiplicity of exposures, and immunosuppression. Colposcopy with cytology and biopsy allows definitive microscopic identification of the virus and serotyping. Aggressive management of both male and female partners will reduce the spread of the virus and reinfection. Successful treatment methods have included cryosurgery; electrocautery; carbon dioxide laser therapy; and use of a keratolytic, cauterizing agent, topical fluorouracil (Efudex), and interferon.
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PMID:Genital warts. Newly discovered consequences of an ancient disease. 277 37

The diagnosis and therapy of human papillomavirus infections in men is of potential benefit because it may decrease the reservoir of virus from which genital condylomata or squamous neoplasia may arise in women. To investigate the efficacy of diagnostic methods, we examined the 127 male sexual partners of 127 women with cervical intraepithelial neoplasia. Eighty-three mostly asymptomatic men (65%) had from one to 50 (median three) small (median 3 mm) human papillomavirus-associated lesions consisting of condylomata (80 cases) and penile dysplasia (three cases). The colposcope aided diagnosis or was necessary for diagnosis of 59% of the lesions. Routine application of 3% or 5% acetic acid yielded white or grayish epithelial changes in 22% of the cases, which would have been missed without this technique. Papular, flat, spiked, and mixed lesions were more common (85%) than papillary changes or classic condylomata acuminata (15%). In contrast to smears from the external penile surface, smears obtained from the male urethra were satisfactory in most cases and yielded positive results in nine men (7%). Condylomata are common in male partners of women with cervical intraepithelial neoplasia, but the lesions are frequently not apparent unless magnification and acetic acid are used. Cytologic smears may aid in the diagnosis of condylomata in the urethra.
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PMID:Human papillomavirus-associated lesions of the penis: colposcopy, cytology, and histology. 281 95

Since the human papillomavirus is transmissible sexually, an ever increasing number of male patients is seen in dermatology departments. It therefore seems to be important to evaluate the frequency of HPV-related genital lesions in both males and females. Several recent studies have made it clear that concomitant lesions are very often observed in sexual partners. We have tried here to summarize the different data reported in the literature concerning the frequency of HPV lesions and their probable role in cervical cancer. Some human papillomaviruses (types 6 and 11) produce benign lesions while others possess an oncogenic potential (types 16 and 18). Thus, men with venereal condylomas may constitute a group at risk of cervical neoplasia for their female partners. Some authors even consider cancer of the cervix as a sexually transmitted disease. It now becomes necessary to undertake systematic examination of male partners in order to detect viral lesions invisible to the naked eye, particularly before and after acetic acid application on the penis and by means of a colposcope. However, for several reasons given in the conclusion, such an epidemiological study remains difficult to perform.
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PMID:[Genital papillomavirus lesions. Coexistence in sexual partners, role in cancer of the cervix and value of colposcopy]. 282 88

The clinical toxicity of acetic acid-treated "Salmonella minnesota" R595 (Re) organisms was evaluated in 24 cancer patients. Bacteria were injected i.v. four times at increasing doses for a total of 6.5 micrograms. This therapeutic regimen was free of major side effects (one patient had fever higher than 38 degrees C and 10 patients complained of pruritus). Furthermore, this bacterial preparation which possesses a more exposed lipid A on its surface, exhibited immunomodulating capacities in that it normalized the inverted T helper/T suppressor ratio and enhanced natural killer activity in tumor patients. The mechanisms of the lower toxicity and immunomodulating activities of these bacteria compared to other lipid A preparations are discussed.
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PMID:Pilot study of intravenous administration of the acid-treated Salmonella minnesota R595 (Re) in cancer patients. 296 Nov 15

An atypical creatine kinase (CK) isoenzyme migrating cathodically to CK-MM in the electrophoresis was observed as response to the embolization of the right hepatic artery in two patients with liver metastasis. The time course of the atypical CK release was compared to that of tumor secretion products, i.e., insulin and 5-hydroxy-in-dol-acetic acid. The CK isoenzyme probably reflects a mitochondrial breakdown of the metastasis in question. The influence of the treatment on liver function was characterized by a marginal augmentation of ASAT and ALAT and by a small but significant leakage of mitochondrial glutamate dehydrogenase. In addition to the atypical CK, CK-BB, and CK-MB isoenzymes were found in the serum of the patient with primary carcinoid carcinoma.
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PMID:Creatine kinase isoenzymes: biochemical findings after therapeutical embolization of the hepatic artery in two patients with liver metastasis of an islet cell carcinoma or a carcinoid tumor. 298 64

The incorporation and turnover of phospholipid precursors in cultured normal and tumoral glial cells was investigated during the plateau phase of growth. Glycerol was incorporated similarly by all cell types, and was renewed with a half-life of 19-37 hr. Acetate had a much longer half-life in primary cultures (50-75 hr) than in proliferative tumor cells (20-40 hr). Phosphate had a more rapid turnover rate in primary cultures (25 hr) than in proliferative tumor cells (50 hr). For all precursors, inositol- and choline phosphoglycerides had a faster turnover rate than other phospholipids.
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PMID:Incorporation and turnover of phospholipid precursors in normal and tumoral glial cells in culture. 299 54


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