Add time:08/04/2019         Source:sciencedirect.com

The carcinostatic activity of a 4-hydroxy 2,3-trans-pent-en-1-al(HPE): cysteine adduct was studied against the ascitic form of Sarcoma 180 both in vitro and in vivo. The effect of HPE treatment in vitro (at concentrations in excess of 0·16 mM) was to depress primarily the incorporation of 3H-thymidine into DNA; 3H-uridine and 3H-leucine incorporations into RNA and protein respectively were considerably less affected. The addition of 0·16 mM cysteine before treatment of Sarcoma 180 cell suspensions with HPE provided partial protection in relation to the depression of 3H-thymidine incorporation. Tumour cell suspensions were preincubated in vitro for 30–120 min at 37°C with 0.04–1.28 mM HPE, HPE-cysteine or cysteine before the addition of 3H-thymidine. The effectiveness of different types of preincubation procedure, in depressing the subsequent incorporation of 3H-thymidine into Sarcoma 180 tumour cells in vitro, were compared. The results obtained indicate that HPE-cysteine was 4–7 times less effective on a molar basis than treatment of tumour cells in vitro with HPE alone.The ld50 in mice for a single i.p. injection of HPE-cysteine was 362 mg/kg body weight (expressed as mg HPE); thus the adduct is approx. 7 times less toxic than the free aldehyde injected i.p. Extensions in survival time were produced by i.p. injection of increasing doses of HPE-cysteine in vivo, in mice bearing the ascitic form of Sarcoma 180. Treated animals received, on days 3–7 following transplantation, a single daily dose of the HPE-cysteine adduct equivalent to a dose of HPE alone of 8–256 mg/kg body weight. Significant increases in survival time were obtained at doses of HPE-cysteine in excess of 32 mg/kg body wt./day. Mice treated with the adduct responded with increases in survival time, compared to untreated control animals, of 50%, 94% and 129% at doses of the adduct equivalent to doses of HPE alone of 64, 128 and 256 mg/kg body wt./day respectively.The results obtained are consistent with the view that the extended breakdown of an adduct of HPE and cysteine, releasing the reactive aldehyde, increases the half-life of HPE both in vitro and in vivo.

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