Repeated Administration Of Compound Research Articles

In vitro antiproliferative effects, toxicity profiles in vivo in mice and antitumour activity in tumour-bearing mice of four diorganotin compounds

The in vitro antiproliferative effects, the in vivo toxicity profiles in mice and the antitumour activity in tumour bearing mice were screened for four novel di-n-butyltin carboxylates, di-n-butyltin bis(2,4-dihydroxybenzoate) [compound 1 (C1)], di-n-butyltin bis(2,5-dihydroxybenzoate) (C2), di-n-butyltin bis(pentafluorophenylacetate) (C3), and bis[di-n-butyl(pentafluorophenylacetato)tin] oxide (C4). All compounds revealed similar in vitro chemosensitivities in two cell lines, C26-10 and C26-A, two murine undifferentiated colon carcinoma cell lines. With all compounds tested, not only was cell growth inhibited in vitro, but also cell kill was achieved. At their maximum tolerated dose (MTD), C1 and C4 were inactive in vivo against colon 26 tumours in Balb/C mice when administered twice with one week interval (qd7x2 schedule). At their MTD, compound 2 (single dose administration and qd7x2 schedule) and compound 3 (qd7x2) showed slight in vivo antitumour activity with a ratio of the relative tumour size of the treated mice to that of control mice (T/C) = ca. 0.6 (T/C less than or equal to 0.6 being the cut-off level for sensitivity). However, the cut-off level for the growth delay factor (GDF) (>1) was not reached. With the exception of C2 administered with a single dose and C3 with the 2 doses protocol, treatment with these compounds did not increase the life span of the mice. Repeated administration of compound 2 did not improve the antitumour activity compared to single dose administration. This was probably due to the higher toxicity when C2 was administered a second time after one week.

Effect of Z-103 on Compound 48/80-Induced Gastric Lesions in Rats

Z-103 (a novel anti-ulcer agent), given p.o. at doses of 30 and 100 mg/kg, significantly prevented gastric lesions induced by compound 48/80 in rats. Z-103 inhibited the histamine release from rat peritoneal mast cells stimulated by compound 48/80 in a dose-dependent manner. Z-103 inhibited the increase in thiobarbituric acid (TBA) reactants induced by a single or repeated administration of compound 48/80 in the gastric mucosa. These observations suggested that the protective effect of Z-103 against compound 48/80-induced gastric lesions may be due to its stabilizing activity toward mast cells and/or an antioxidative effect on the gastric mucosa.

Pathogenesis of compound 48/80-induced gastric lesions in rats.

Intraperitoneal administration of 0.75 mg/kg of compound 48/80 (a mast cell degranulator) once daily for four days induced extensive gastric lesions in rats. Oral administration of tripelennamine (histamine H1-receptor antagonist) and cimetidine (histamine H2-receptor antagonist) twice daily for four days had little or no effect on the lesion formation. Oral administration of methysergide and cyproheptadine (serotonin antagonists) and FPL-52694 (a mast cell stabilizer) potently inhibited the compound 48/80-induced lesions. Intraperitoneal administration of histamine plus serotonin, or serotonin alone, induced gastric lesions which resembled those induced by compound 48/80. These lesions were potently inhibited by methysergide and cyproheptadine, but not by tripelennamine, cimetidine, and FPL-52694. Single or repeated administration of compound 48/80 significantly increased serum histamine and serotonin levels. After a single administration of compound 48/80, the increased histamine levels rapidly returned to normal levels, but serotonin levels remained high for 7 hr. Histamine and serotonin levels in the gastric mucosa were transiently increased after a single administration of compound 48/80, but remained normal after repeated administration. Single or repeated administration of compound 48/80 had little effect on arterial blood pressure. The compound 48/80-induced gastric lesions appear to be caused primarily by the release of serotonin, but not histamine, from extragastric sources.