Biomedical subjects

D Smithers

Publications and source records attributed to D Smithers.

18 recordsLinked to original sources

PubMed1994

Endocrine changes with the aromatase inhibitor fadrozole hydrochloride in breast cancer.

Fadrozole hydrochloride is a potent aromatase inhibitor with proven clinical effectiveness. However, its optimal dose and its effects on serum aldosterone levels/electrolyte balance have been disputed. To resolve these issues, a double-blind randomised endocrine study of three doses of fadrozole hydrochloride [0.5 mg twice daily (bd); 1.0 mg bd; 2.0 mg bd] was conducted in 80 (68 evaluable) postmenopausal patients with advanced breast cancer over a period of 3 months. There were substantial falls in the serum levels of oestradiol, oestrone and oestrone sulphate. For oestrone only, there was a significant effect of dose (on-treatment means: 0.5 mg, 38.0 pmol/l; 1.0 mg, 25.0 pmol/l; 2.0 mg, 23.9 pmol/l). All oestrogens showed a similar pattern in relation to time, with the 3-month mean being higher than those at 1 and 2 months, and this was significant for oestradiol (P = 0.012). There was an indication that complete suppression of oestradiol and oestrone was not maintained throughout the 12-h dosing period, but the data and its interpretation are complicated by a minor diurnal rhythm in these parameters. There were significant increases in 17-hydroxyprogesterone and androstenedione which may be due to a block of 11 beta-hydroxylase. There was a statistically non-significant fall in aldosterone levels (P = 0.06) during treatment (median pretreatment, 446 pmol/l; median decrease, 125 pmol/l). However, the concurrent significant fall in the plasma sodium: potassium ratio indicated that changes in aldosterone secretion did occur. None of these effects on adrenal pathways was of a degree which is likely to have clinically relevant consequences. It is concluded that fadrozole hydrochloride achieves near maximal suppression of oestrogens at 1 mg bd, and that its effects on aldosterone synthesis are unlikely to be of clinical significance.

Adult↗

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↗

PubMed1984

Mode of action of 2-amino-6-chloro-1-deazapurine.

2-Amino-6-chloro-1-deazapurine is of interest as a purine analog with demonstrated in vivo activity against mouse leukemia L1210. That the active form of this agent is a nucleotide and that the nucleotide is formed by the action of hypoxanthine (guanine) phosphoribosyltransferase were shown by the facts that (a) L1210 cells deficient in hypoxanthine phosphoribosyltransferase were insensitive to the analog; (b) hypoxanthine, but not adenine, prevented the formation of the analog nucleotide by enzyme preparations containing activities of both hypoxanthine and adenine phosphoribosyltransferases; and (c) the cytotoxicity of the analog was prevented by hypoxanthine. The ribonucleoside of this analog was not toxic to cell cultures and hence is not phosphorylated or cleaved to the base. In intact HEp-2 cells and L1210 cells, the analog was metabolized to the nucleoside 5'-phosphate which accumulated to concentrations as high as 1000 nmoles/10(9) cells; no di- or triphosphates were detected. In HEp-2 cells, the analog reduced the pools of purine nucleotides with some accumulation of IMP. The toxicity of minimal inhibitory concentrations of the analog to HEp-2 cells could be prevented or reversed by 4(5)-amino-5(4)-imidazolecarboxamide (AIC); the toxicity of higher concentrations could be prevented or reversed by a combination of adenine and guanosine but not by AIC. The analog inhibited the incorporation of formate into purine nucleotides and into macromolecules at concentrations that had no effect on utilization of hypoxanthine; at higher concentrations the incorporation of hypoxanthine was inhibited. Low concentrations also inhibited the utilization of uridine and thymidine. The incorporation of hypoxanthine and AIC into guanine nucleotides, but not adenine nucleotides, was inhibited. These results indicate two sites of inhibition of the biosynthesis of purine nucleotides, the more sensitive one being on an early step of the pathway and the less sensitive one on the IMP-GMP conversion. That the blockade of de novo synthesis probably was at the site of feedback inhibition was indicated by the fact that the analog inhibited the accumulation of formylglycinamide ribonucleotide in azaserine-treated cells but did not inhibit the synthesis of 5'-phosphoribosyl 1-pyrophosphate. Comparative studies were performed with the related analog, 2-amino-6-chloropurine, which has been reported to produce a similar dual blockade of the purine pathway. This purine was less toxic than its 1-deaza analog; it produced a modest decrease in adenine nucleotides but increased pools of guanine nucleotides.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Aminopurine↗

PubMed1983