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Biomedical subjects

L M Rose

Publications and source records attributed to L M Rose.

82 records · Page 5Linked to original sources
PubMed1975

The mechanism of action of 3-deazauridine in tumor cells sensitive and resistant to arabinosylcytosine.

Deazauridine inhibited growth of tumor cells in culture and in culture and in vivo; this agent was significantly more effective against L1210/AraC than against the parent sensitive line. Inhibition of growth of tumor cells in culture was prevented by uridine and cytidine and was partially alleviated by deoxycytidine, but not by deoxyuridine or thymidine. DeazaUR inhibited nucleic acid synthesis but not protein synthesis in tumor cells in culture; deoxycytidine alleviated inhibition of nucleic acid synthesis. The labeling of pyrimidine ribonucleotides by 6-14C-orotic acid was inhbited by deazaUR. DeazaUR treatment of tumor cells in culture resulted in increased uptake of cytidine-3H into RNA, whereas uridine-3H uptake into RNA was inhibited. Labelling of DNA by uridine-3H/ and cytidine-H was inhibited by deazaUR. Pools of CMP, CDP, and CTP decreased markedly during deazaUR treatment of L1210 cells in culture and in vivo. These observations in growing cells pointed to deazaUR inhibition of the synthesis of cytidylic acid. Deazauridine 5'-triphosphate was found to be an inhibitor of the synthesis of CTP from UTP catalyzed by enzyme preparations from L1210 cells. This observation is in agreement with those of McPartland et al.19 that deazaUTP inhibited CTP synthetase purified from calf liver. Deazauridine treatment of L1210 cells in culture stimulated the uptake of deoxycytidine-3H into DNA while inhibiting the uptake of 3H-labeled deoxyuridine, thymidine, deoxyadenosine, and deoxyguanosine. Intracellular pools of dCTP were decreased by deazauridine treatment in L1210 cells in culture and in vivo. Deazauridine 5'-diphosphate inhibited the enzymatic reduction of pyrimidine ribonucleoside 5'-diphosphates to the corresponding deoxyribonucleotides. These results are consistent with the view that deazauridine, after its uptake and intracellular phosphorylation, strongly inhibits the formation of CTP. This is considered to be the primary metabolic effect of the analog. A secondary effect appears to be an inhibition of dCTP formation.

3-Deazauridine↗
PubMed1975

Hydroxy derivates of S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate and related compounds as antiradiation agents.

The high antiradiation activity and low toxicity of sodium 3-amino-2-hydroxypropyl hydrogen phosphorothioate (1) suggested the introduction of hydroxyl groups into other types of radioprotective phosphorothioates. A number of such compounds were synthesized, including S-3-(3-aminopropylamino)-2-hydroxypropyl dihydrogen phosphorothioate (11, n equals 3), S-2-(3-amino-2-hydroxypropylamino)ethyl dihydrogen phosphorothioate (20) and its propyl homolog 26, N,N'-(2-hydroxytrimethylene)bis(S-2-aminoethyl dihydrogen phosphorothioate) (40), S-2-[3-(2-hydroxyethylamino)propylaminoi1ethyl dihydrogen phosphorothioate (44), and sodium S-2-amino-2-(hydroxymethyl)-3-hydroxypropyl hydrogen phosphorothioate (49). Compounds 11 (n equals 3), 20, 26, and 49 were highly protective when administered intraperitoneally but were generally ineffective when given perorally, as were the other hydroxylated phosphorothioates prepared. The introduction of hydroxyl groups significantly enhanced the radioprotective properties of nonhydroxylated parent compounds, however, only in the case of intraperitoneally administered.

Administration, Oral↗
PubMed1975

Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine.

The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.

Azaguanine↗
PubMedDate not supplied

Using the GOHAI to assess oral health status of frail homebound elders: reliability, sensitivity, and specificity.

A pilot study assessed the clinically determined and self-reported oral health status of 50 randomly selected homebound patients served by Boston's Home Medical Service. The sample was largely female, low-income, and edentulous. The median age of the patients was 81 years (range, 64-101). While 76% deemed themselves to be in good to excellent oral health, 80% of the patients had not seen a dentist within the last two years, and 80% were found to be in need of routine dental care. To assess whether the Geriatric Oral Health Assessment Index (Atchison and Dolan, 1990) could be used by non-dental health professionals to determine the need for requesting dental consultation, the study physician repeated the administration of the GOHAI for 23 of the 50 subjects within eight weeks of the initial examination. For the 23 subjects having both dentist- and physician-administered GOHAI scores, the intraclass correlation coefficient was r = 0.61 (p = 0.002), indicating good agreement between the dentist's and physician's administrations of the GOHAI. However, given the high prevalence of need for care, the GOHAI appears to be of less value than an examination for identifying persons who need dental care in this population. Future research is needed to examine the GOHAI's sensitivity and specificity in populations with low to moderate prevalence of treatment need.

Aged↗
PubMedDate not supplied

Disposition and metabolism of carbovir in mice dosed intravenously or orally.

To determine the disposition of carbovir and [3H]carbovir in mice, HPLC and thin-layer chromatographic assays were developed and mice were dosed iv and by gavage. Carbovir had no lethal effect at iv doses up to 500 mg/kg and was stable for 24 hr in mouse plasma at temperatures ranging from 0-37 degrees C. Binding to plasma proteins was minimal. Following an iv dose of 500 mg/kg of carbovir or [3H] carbovir, elimination phases with half-lives of 26-37 min (alpha) and 206-330 min (beta) were observed for plasma. For mice dosed with 27 mg/kg of [3H]carbovir, however, only a single phase with a half-life of 17 min was noted. Of several tissues examined, kidney contained the highest concentration of radioactivity. For the high dose, 19.0 +/- 2.6% was excreted in the urine in 24 hr as unchanged carbovir and 42.2 +/- 2.4% as metabolites; for the low dose, 54.5 +/- 6.1% was excreted as carbovir and 26.5 +/- 5.0% as metabolites. When mice were dosed orally with 500 mg/kg, plasma concentrations of carbovir were low. The initial plasma half-life for carbovir was 69 min; the terminal half-life was 822 min. Urinary excretion of unchanged carbovir was 21.3 +/- 7.1%. These results indicate that clearance of high doses of carbovir is limited and that its absorption is poor after oral dosing.

Administration, Oral↗
PubMedDate not supplied

Disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine in mice, dogs, and monkeys.

The metabolic disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-AraA) has been studied in mice, dogs, and monkeys after iv administration. Following injection of 2-F-AraA (30 mg/m2) into mice, serum levels fell with apparent half-lives of 17 min for the alpha-phase and 72 min for the beta-phase. For dogs given the same dose, these values were less than 5 and 112 min, and, for monkeys, 26 and 125 min, respectively. A higher concentration of metabolites was present in the serum of dogs than in the serum of mice and monkeys. Phosphorylated derivatives of 2-F-AraA were present in each of several mouse tissues examined; liver contained the highest concentration. In 24 hr, mice excreted more than half of the administered compound in the urine as unchanged 2-F-AraA. For dogs given a dose of 400 mg/m2, a single phase of disappearance of the drug (t1/2 = 130 min) was observed. For a single monkey, there were two phases, with half-lives of 15 min and 6.7 hr. In the urine, monkeys excreted about half of either dose as parent compound; but dogs excreted only about one-fourth as unchanged drug. These data indicate that 2-F-AraA is extensively metabolized by dogs but less so by mice and monkeys.

Animals↗
PubMedDate not supplied

Metabolism and disposition of a thiazolobenzimidazole active against human immunodeficiency virus-1.

This study was undertaken to evaluate the disposition of the thiazolobenzimidazole, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TZB), which has promising antiviral activity. For mice, the maximum tolerated intravenous dose of TZB was 50 mg/kg. An HPLC procedure developed for TZB was used to determine the distribution of the drug. TZB showed no measurable binding to plasma proteins. With intravenous dosing, the kinetic values for TZB in plasma and in each of five tissues were similar in that there was an initial, short alpha-phase (1.8-7.2 min) and a longer beta phase (38-68 min). The concentrations in liver were higher than those in plasma and other tissues. For mice dosed subcutaneously with TZB, the AUC value for plasma was considerably lower than that for mice dosed intravenously; mice dosed intraperitoneally had higher plasma levels of the drug than after oral or subcutaneous dosing. No intact drug could be detected in the plasma of mice dosed topically. After intravenous, oral, or subcutaneous dosing, urinary excretion of intact TZB was < 2% of the dose. Of several vehicles tested in an attempt to increase the plasma levels of unchanged TZB in mice dosed orally, 40% hydroxypropyl beta-cyclodextrin was most effective. Two metabolites present in plasma and urine of mice were tentatively identified as the axial and equatorial sulfoxide isomers of TZB; a third, minor metabolite, was tentatively designated as the sulfone. Although the compound has activity against HIV-1, its low solubility and extensive metabolism reduce its potential for clinical use.

Administration, Oral↗