Search PubMed⌕ Search

Biomedical subjects

H J Thomas

Publications and source records attributed to H J Thomas.

At least 37 records · Page 2Linked to original sources
PubMed1991

The genetics and molecular biology of colorectal cancer.

Progress has continued in explicating the genetics of inherited predispositions to colorectal cancer and the molecular events that lead to tumorigenesis. New polymorphic DNA markers have been described for the presymptomatic diagnosis of familial adenomatous polyposis and a candidate gene has been characterized. Pedigree studies have suggested that there may be an inherited predisposition to many apparently nonfamilial colorectal cancers and a genetic model of tumorigenesis in common colorectal cancer has been proposed that includes the activation of dominantly acting oncogenes and the inactivation of growth suppressor genes. Two features of colorectal cancer make it a particularly good model for studying neoplasia. There are several well-defined rare inherited syndromes that predispose to the development of colorectal cancer in an autosomal dominant manner, and the majority of carcinomas are thought to arise from preexisting benign adenomatous polyps, allowing the analysis of genetic changes during tumorigenesis.

Adenomatous Polyposis Coli↗
PubMed1990

The assignment of the genes coding for human complement components C6 and C7 to chromosome 5.

A panel of 19 somatic cell hybrids was tested for the presence of human sequences coding for complement components C6 and C7 by restriction enzyme digestion and Southern blots probed with human C6 and C7 cDNA probes. C7 was also detected by amplifying part of the human gene in hybrid DNA using the polymerase chain reaction. Detection of human C6 and C7 was completely correlated with the presence of chromosome 5.

Animals↗
PubMed1990

The genetics of colorectal cancer.

Two features of colorectal cancer have greatly aided the recent progress in understanding its genetics: firstly the majority of colorectal cancers arise from premalignant adenomatous polyps allowing the analysis of somatic genetic changes during tumorigenesis, and secondly there are several well defined inherited syndromes that predispose to colorectal cancer in an autosomal dominant manner. The familial polyposis gene has been mapped to chromosome 5q and loss of material on chromosome 5 shown in a large proportion of sporadic (non-familial) adenomas and carcinomas. Allele loss has also been found in a high proportion of colorectal cancers on chromosomes 17 and 18 and the respective genes involved identified as that coding for the oncoprotein p53 on 17p and the DCC ('deleted in colorectal carcinomas') gene on 18q. In addition activation of k-ras is found frequently in colorectal adenomas and carcinomas. The development of colorectal neoplasia is associated with the accumulation of genetic changes. Family studies of apparently sporadic colorectal cancer probands have shown an increased incidence of adenomas and carcinomas in first degree relatives. More recently pedigree studies have suggested that an inherited predisposition may be responsible for the majority of colorectal tumours.

Chromosome Aberrations↗
PubMed1989

CpG island clones from a deletion encompassing the gene for adenomatous polyposis coli.

Adenomatous polyposis coli (APC), a dominantly inherited disorder, has been mapped to chromosome 5q15-q21 by family linkage studies. Cells from patients with deletions in this region, in one case associated with polyposis in a family, have been used to construct human hamster hybrid cell lines that retain either the normal or deleted chromosome 5. These lines have been used to identify markers from the region of the polyposis gene obtained by cloning the ends of 0.5- to 2-megabase BssHII fragments purified by pulsed-field gel electrophoresis. Three markers are described that map within the deletions and must therefore be close to the APC gene.

Adenoma↗
PubMed1988

Nitrosoureido nucleosides as potential inhibitors of nucleotide biosynthesis.

Several nitrosoureido nucleosides (3a, 3b, 5a, 7a, 7c, and 10a) designed as inhibitors of enzymes that metabolize pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The methylnitrosoureas 3a and 3b were not significantly cytotoxic to H.Ep.-2 and L1210 cells in vitro but showed moderate activity in the P388 mouse leukemia screen (79% ILS for 3a and 56% ILS for 3b). The (chloroethyl)nitrosoureas 7a and 7c inhibited proliferation of L1210 cells, were cytotoxic to H.Ep.-2 cells, and demonstrated good activity against P388 in vivo (135% ILS with one 30-day survivor for 7a and 191% ILS with two 30-day survivors for 7c). Overnight exposure of L1210 cells to 7a and 7c resulted in cell enlargement accompanied by cell lysis. Macromolecular synthesis in enlarged cells, particularly RNA and protein synthesis, was markedly increased relative to that in untreated control cells. The half-lives of each of the nitrosoureas in pH 7 buffer was determined and compared with biological activity.

Animals↗
PubMed1987

5-Amino-4-(diazoacetyl)-1-beta-D-ribofuranosylimidazole, a new antileukemic agent.

5-Amino-4-(diazoacetyl)-1-beta-D-ribofuranosylimidazole (15), 5-amino-4-(chloroacetyl)-1-beta-D-ribofuranosylimidazole (16), and a number of related imidazole ribonucleosides have been synthesized. Compounds 15 and 16 are cytotoxic to both H.Ep.-2 and L1210 leukemia cells in culture. The (diazoacetyl)imidazole 15 is also active against the P388 leukemia in mice.

Aminoimidazole Carboxamide↗
PubMed1987

A study of the use of intravenous cannulas for medical emergencies in Newham--implications for financial savings.

A study of intravenous (i.v.) cannula usage for medical emergencies admitted to hospitals in the Newham Health District was undertaken during two defined periods (24 and 35 days). Almost half the cannulas inserted (47%) were not flushed following an initial bolus injection of heparinized saline. The duration that cannulas remained in a vein ranged from 24 hours to 8 days (median 2 days) and inflammation around the cannula site was related to the length of time since insertion but unrelated to whether the cannula was flushed regularly or to the type of fluid used. Our findings indicate a substantial wastage of i.v. cannulas due to difficulties with insertion and suggest that isotonic saline, without heparin, is effective in maintaining cannula patency for 48 hours. It is concluded that these findings are not unique to the Newham Health District and worthwhile financial savings should be achieved throughout the NHS if clinicians reconsider the indications and use of i.v. cannulas for their patients.

Adolescent↗
PubMed1985

Metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine.

The metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine were studied to elucidate the biochemical basis for their known cytotoxicities. 2-Azaadenosine is a known substrate for adenosine kinase. That 2-azahypoxanthine is a substrate for hypoxanthine (guanine) phosphoribosyltransferase is shown by the observations that, in cell-free fractions from HEp-2 cells supplemented with 5-phosphoribosyl-1-pyrophosphate, 2-azahypoxanthine inhibited the conversion of hypoxanthine to IMP but not the conversion of adenine to AMP, and hypoxanthine, but not adenine, inhibited the conversion of 2-azahypoxanthine to 2-azaIMP. [8-14C]2-Azahypoxanthine was synthesized from [8-14C]hypoxanthine via [2-14C]-4-amino-5-imidazolecarboxamide. In HEp-2 cells in culture, the principal metabolite of [8-14C]-2-azahypoxanthine was 2-azaATP; there was no detectable 14C in deoxynucleotides or in DNA or RNA fractions. 2-Azaadenosine was much more toxic than 2-azahypoxanthine, and, when used in the presence of an adenosine deaminase inhibitor, 2'-deoxycoformycin, was converted in HEp-2 cells to 2-azaATP in amounts that exceeded those of ATP in control cells. The pool of ATP was reduced by as much as 75% as 2-azaATP accumulated. In a short-term experiment (4 hr), 2-azaadenosine selectively reduced the pools of adenine nucleotides, whereas 2-azahypoxanthine reduced the pools of guanine nucleotides selectively. Both 2-azahypoxanthine and 2-azaadenosine inhibited the incorporation of formate into purine nucleotides and were without effect on the conversion of thymidine and uridine to nucleotides. 2-Azahypoxanthine inhibited the incorporation of thymidine into macro-molecules but not that of uridine or leucine; 2-azaadenosine inhibited the incorporation of all three of these precursors non-selectively. 2-AzaIMP inhibited IMP dehydrogenase competitively with IMP (Ki = 66 microM). The difference in effects of 2-azahypoxanthine and 2-azaadenosine perhaps may be due to the production, from 2-azahypoxanthine but not from 2-azaadenosine + 2'-deoxycoformycin, of 2-azaIMP, which inhibits synthesis of guanine nucleotides and thereby results in inhibition of DNA synthesis. Specific sites of action for 2-azaadenosine are yet undefined.

Adenosine↗
PubMed1985

Study on the inhibition of adenosine deaminase.

4(R)-(1-Hydroxyethyl)-5-methyl-1-beta-D-ribofuranosylimidazole (10), which contains only the asymmetric alcohol center of the diazepinol ring of the adenosine deaminase inhibitor coformycin (12), is a much less potent inhibitor of the enzyme but still binds to the enzyme about as tightly as the normal substrate.

Adenosine↗
PubMed1984

Potential inhibitors of nucleotide biosynthesis. 2. Halomethyl ketone derivatives of pyrimidine nucleosides.

Several halomethyl ketone derivatives of pyrimidine nucleosides have been prepared for evaluation as cytotoxic agents. The first series are 1-(8-halo-2,5,6,8- tetradeoxy -beta-D-erythro-oct-7 - ulofuranosyl )thymines (7-9), whereas the second type are halo derivatives of acetophenone (12-14 and 16). These compounds are cytotoxic, and one (13) showed activity against the P388 leukemia in vivo.

Animals↗
PubMed1982

Carbocyclic analogue of 3-deazaadenosine: a novel antiviral agent using S-adenosylhomocysteine hydrolase as a pharmacological target.

The carbocyclic analogue of 3-deazaadenosine (3-deaza-C-Ado) has been synthesized and found to have antiviral activity in cell culture against herpes simplex virus type 1, vaccinia virus, and HL-23 C-type virus. It is relatively noncytotoxic at effective antiviral concentrations and is not subject to deamination or phosphorylation. It acts as a competitive inhibitor of S-adenosyl-L-homocysteine hydrolase, is at best a poor substrate, and does not inactivate the enzyme significantly. 3-Deaza-C-Ado may cause a selective inhibition of the methylation of the polynucleotide 5' cap of viral mRNA via higher cellular concentrations of S-adenosyl-L-homocysteine, resulting from the inhibition of S-adenosylhomocysteine hydrolase in infected cells, since increases in the intracellular level of S-adenosylhomocysteine, but no effects on DNA or RNA synthesis, were observed after incubation of these cells with it.

Adenosylhomocysteinase↗
PubMed1981

Potential inhibitors of nucleotide biosynthesis. 1. Nitrosoureidonucleosides. 2.

Several nitrosoureidonucleosides (9a, 9b, 11a, 11b, 18 and 20) designed as inhibitors of enzymes that metabolize purine and pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The low level of biological activity observed may be due to the unexpected stability of these nitrosoureas compared to biologically active compounds such as N-methyl-N-nitrosourea (MNU), N,N'-bis(2-chloroethyl)-N'-nitrosourea (BCNU), and N,N'-dicyclohexyl-N-nitrosourea (DCyNU).

Animals↗
PubMed1979

Phosphonate analogue of 2'-deoxy-5-fluorouridylic acid.

The phosphonate analogue (6) of 2'-deoxy-5-fluorouridylic acid has been prepared via a Pfitzner--Moffatt oxidation and Witting reaction. This compound was found to inhibit thymidylate synthetase from three sources and to be cytotoxic to H.Ep.-2 cells in culture.

Antineoplastic Agents↗
PubMed1979

Nitrosoureidonucleosides.

3-Deoxyl-1,2-O-isopropylidine-3-(3-methylureido)-alpha-D-ribofuranose (2) was converted to 1,2,5-tri-O-acetyl-3-deoxy-3-(3-acetyl-3-methylureido)-D-ribofuranose (4) and the corresponding glycosyl chloride (7). These sugars were converted to the 3-deoxy-3-(3-methylureido)-beta-D-ribofuranosyl derivatives of adenine (6c), 2-chloroadenine (6d), cytosine (6f), and uracil (6g). Nitrosation of these nucleosides gave the corresponding 3-methyl-3-nitrosoureidonucleosides 8c,d,f,g. 5'-Amino-5'-doxyadenosine (10a), 5'-amino-5'-deoxyuridine (10b), and 5'-amino-5'-deoxycytidine (10c) were all converted to the corresponding 5'-(methylureido)-5'-deoxynucleosides 15a--c by reaction with methyl isocyanate. Nitrosation of these compounds gave the methylnitrosoureidonucleosides 16a--c. These nitrosoureas, potential active-site-directed irreversible enzyme inhibitors, showed little cytotoxicity or activity against leukemia L1210 in vivo.

Animals↗