מתוך medicontext.co.il
By Will Boggs, MD
WESTPORT, CT (Reuters Health) – Antitumor agents derived from 2-acetylpyridine inhibit colon cancer cells in vitro and in nude mice through a novel mechanism of action, according to a report in the October 1st International Journal of Cancer.
"The new compounds seem to be interesting for the treatment of these tumors," Dr. Johann Hofmann from the University of Innsbruck, Austria, told Reuters Health.
2-acetylpyridine, like hydroxyurea, works by inhibiting ribonucleotide reductase, but its high in vivo toxicity has precluded its use as a clinical antitumor agent, the authors explain.
Dr. Hofmann and associates synthesized several new compounds in which the toxic benzothiazole ring of 2-acetylpyridine was replaced by benzoxazolyl or benzimidazolyl. Three of the compounds (EPH52, EPH61, and EPH116) exhibited remarkable in vitro potency against three colon carcinoma cell lines, the authors report.
All three compounds also inhibited small cell lung carcinoma cell proliferation, the report indicates, and EPH52 and EPH116 showed above-average inhibition of melanoma cell lines.
Compared with no treatment, EPH116 inhibited the growth of human colon tumor xenografts in nude mice by 38% at a 20 mg/kg dose and by 64% at 40 mg/kg, the maximally tolerated dose, the researchers note. EPH116 proved to be a potent inducer of apoptosis in Burkitt's lymphoma cells, but treatment with EPH116 did not arrest cells in S-phase as would be expected with ribonucleotide reductase inhibition.
How EPH116 induces apoptosis is not yet clear. "We only know that the mechanism is different from that of 175 standard tumor agents," Dr. Hofmann said.
"We have several compounds which seem to have better antitumor effects than those published in this manuscript," Dr. Hofmann said. "Further investigation of at least two compounds will show whether they are worth [developing] further or whether it is better to synthesize derivatives of the compounds and screen those for their antitumor activity."
The development of these new drugs is currently plagued by a lack of grant support and the need to complete an expensive patenting process before attracting commercial interest, Dr. Hofmann explained. "Although we think that these are interesting compounds and we try everything to develop them further, at present I am not optimistic," he said. "It may be that we will have to shut down the research on these compounds completely."
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