Evaluation of toxicity of beta-tethymustine, a new anticancer compound, in mice.

The toxicity of beta-tethymustine, a potential anticancer compound 1 ((Cancer Lett., 119 (1997) 7-12) was assessed in normal as well as in Ehrlich ascites carcinoma (EAC), Sarcoma-180 (S-180) and Dalton' s Lymphoma (DL) tumour-bearing Swiss male mice by measuring drug-induced changes in haematological parameters, femoral bone marrow cellularity and splenic cellularity on days 9, 15 and 21 following drug treatment at the optimum dose of 8.0 mg/kg body weight from days 1 to 7. Detailed studies were also made by noting sequential changes in the above parameters in normal and EAC-bearing mice on days 12 and 18, respectively. The results indicate that the compound did not adversely affect haematopoiesis as it was observed that no significant decrease in haematological parameters and femoral marrow cellularity occurred in treated groups. Initial hyposplenic activity was, however, noted in EAC and normal treated groups on day 9 which soon reached normal count within 7-10 days after termination of drug therapy. Drug-induced hepatotoxicity and nephrotoxicity were also sequentially evaluated in normal and tumour-bearing mice on days 9, 15 and 21 but no such toxicities were detected. Also, body weight, skin and hair texture, and behavioural pattern (food and water intake and activity) did not reflect any toxic reaction in host mice at this optimum dose.

Evaluation of beta-tethymustine, a new anticancer compound, in murine tumour models.

beta-Tethymustine, 1-[2- {bis(2'-chloroethyl)amino}ethyl]spiro[imidazolidine-4,2'-(1'H),3',4'-dihydronaphthalene]-2,5-dione, has been synthesised and LD50 value determined in Swiss male mice, which was found to be 100.00 mg/kg by single i.p. injection. The following three criteria, namely ascites cell count, ascites fluid measurement and increase in median survival times (MST) of drug-treated (T) over untreated control (C) mice, were studied for evaluation of its antitumour efficacy in vivo in three murine ascites tumours, namely Ehrlich ascites carcinoma (EAC), sarcoma-180 (S-180) and Dalton's lymphoma (DL). At the optimum dose range of 8.0 mg/kg (higher) to 4.0 mg/kg (lower) for 1-7 days treatment following tumour transplantation on day 0, it exhibited a very high percentage of inhibition of both the ascites cell and fluid in these models and displayed excellent ILS(max) value of 80 in EAC, 224 in S-180 and 240 in DL, respectively, showing 'curative' effect (2-3/6 mice having 90 days survival rate). It also demonstrated a high ILS value of 150 with one cure/six mice bearing S-180 for 6 days prior to drug therapy. Screening results were compared with two clinical drugs, cyclophosphamide and 5-fluorouracil, serving as positive controls. Its chemical alkylating activity was compared with nor-HN2 (NSC 10873) and spiromustine (NSC 172112). The results indicate that it possesses greater alkylating activity than nor-HN2 and comparable activity with spiromustine.

Evaluation of phthalmustine, a new anticancer compound. II. Tumor inhibitory effect in murine Ehrlich ascites carcinoma and sarcoma-180.

The antitumor activity of phthalmustine (Neoplasma, 41, 1994, 35) has been evaluated in murine Ehrlich ascites carcinoma (EAC) and sarcoma-180 (S-180). The hematological changes associated with the application of phthalmustine were also evaluated in tumor bearing as well as in normal male Swiss mice. The results indicate that phthalmustine induces marked inhibition of tumor growth and substantially prolongs host survival having curative effect while it does not adversely affect hematopoiesis at the optimum dose tested. No toxic symptoms were noted with respect to external appearance, body weight changes and behavioral pattern.

Evaluation of toxicity of cypenhymustine, a new anticancer compound, in mice.

The toxicity of cypenhymustine, a potential anticancer compound 1 (Cancer Letters, 70 (1993) 1-6), was assessed in normal as well as in Ehrlich ascites carcinoma (EAC), Sarcoma-180 (S-180) and Dalton's lymphoma (DL)-bearing Swiss male mice by measuring drug-induced changes in (1) hematological parameters and (2) femoral bone marrow cellularity on day 9 following drug treatment at the optimum dose of 3.0 mg/kg body weight from days 1 to 7. Detailed studies were also made by noting sequential changes in the above parameters in normal and EAC-bearing mice on days 12, 15, 18 and 21, respectively. The results indicate that the compound did not adversely affect hematopoiesis. From the sequential studies, it was observed that after a mild initial decrease in hematological counts, particularly in EAC-bearing treated mice, normalcy was reached within 11-14 days after termination of drug therapy. Drug induced hepatotoxicity and nephrotoxicity were also sequentially evaluated in normal and EAC-bearing mice on days 9, 12 and 15 but no such toxicities were detected. Also, body weight, skin and hair texture, and behavioural pattern (food and water intake and activity) did not reflect any toxic reaction in the host mice at this optimum dose.

Evaluation of 'cypenhymustine', a new anticancer compound, in murine tumour models.

'Cypenhymustine', 3-[2-[bis(2'-chloroethyl)-amino] ethyl]-5,5- tetramethylenehydantoin, has been synthesised as a potential analog of spiromustine (NSC 172112). The LD50 value was determined in Swiss male mice and found to be 65.0 mg/kg by single i.p. injection. In in vivo screening experiments, three parameters, namely, ascites cell count, ascites fluid measurement and increase in life span (ILS) of drug-treated over control Swiss mice were studied in three murine ascites tumours namely Ehrlich ascites carcinoma (EAC), sarcoma-180 (S-180) and Dalton's lymphoma (DL). Cypenhymustine exhibited a very high percentage of inhibition of both the ascites cell and fluid in these models and also displayed excellent reproducible ILS activity (ILS values of 151 in EAC, 157 in S-180 and 181 in DL at the optimum dose of 3 mg/kg for days 1-7 treatment following tumour transplant on day 0) having a 'curative' effect (1-2 animals: 6 having > 60 days survival rate). The chemical alkylating activity has been compared with spiromustine and another antitumour agent namely nor-HN2.

Hormone mediated changes of brain glutamic acid system in amino acid imbalance.

The effects of adrenal cortical hormone and thyroxine on brain glutamic acid, gamma-amino butyric acid (GABA) and glutamine were studied in rats fed on the amino acid imbalanced diet (8% casein diet supplemented with 0.3% L-threonine). The studies revealed that the decrease in brain glutamic acid and GABA levels in threonine imbalance was recovered by hydrocortisone supplementation. The increased level of brain glutamine in threonine imbalance could not, however, be reversed by hydrocortisone supplementation. Thyroxine supplementation was found to have no impact on any of the members of glutamic acid family in the brain of rats receiving the threonine-imbalanced diet. It was suggested that the decreased levels of brain glutamic acid and GABA in threonine imbalance were caused by diminished adrenal cortical function and the influence of adrenal cortical hormone could be suggested to reside at the level of formation of both glutamic acid and GABA.

Impact of amino acid imbalance on brain amines.

The brain levels of serotonin (5-HT), norepinephrine (NE) and dopamine (DM) were studied in amino acid imbalance, induced in rats by feeding them an 8% casein diet supplemented with 0.3% L-threonine. In addition, tryptophan hydroxylase (TPH) and monoamine oxidase (MAO) activities in the brain were measured. The studies revealed that induction of amino acid imbalance decreased the brain levels of 5-HT and NE, and increased the DM level significantly. These changes in the amine levels were found to be accompanied by increases in the activities of TPH and MAO of brain. It has been suggested that the enhanced activity of brain TPH in threonine imbalance was probably brought about by a conformational change of the enzyme protein and might be an adaptive response to the low level of 5-HT in the brain due to increased MAO activity. The increased brain DM level in threonine imbalance could be ascribed to enhanced entry of tyrosine in the catecholamine anabolic pathway, while the diminished brain NE level under the same condition might result from its increased degradation or diminished conversion of DM to NE due to supposedly inhibition of DM-beta-hydroxylase.

Studies on certain drug-metabolizing enzymes in deoxypyridoxine-treated rats.

The effect of deoxypyridoxine on the activities of drug-metabolizing enzymes was investigated in male rats. Phenylbutazone oxidase and aminopyrine N-demethylase decreased in both liver and kidney of deoxypyridoxine-treated rats that received either an 18% or 8% casein diet. However, the magnitude of decrease in activities was more when the rats received an 8% casein diet. The NADPH oxidase activity remained unchanged following deoxypyridoxine treatment. The diminished activities of phenylbutazone oxidase and aminopyrine N-demethylase noted after deoxypyridoxine treatment were restored by pyridoxine supplementation. The decreased activities of drug-metabolizing enzymes in deoxypyridoxine treated rats were not reversed by thyroxine supplementation. It is suggested that pyridoxine in the form of pyridoxal phosphate might be involved in the regulation of drug-metabolizing activities.