Evaluation of dimethoxydop-NU as a novel anti-tumor agent.

Dimethoxydop-NU, 1-[2-{3-(2-Chloroethyl)-3-nitrosoureido}ethyl]-3,4-dimethoxy-benzene (Compound 1), was synthesized from 3,4-dimethoxy-phenethylamine as a novel anti-tumor agent based on the structures of the clinical drug CCNU and dopamine, an important endogenous biological amine having anti-angiogenesis property. In vitro screening in two human tumor cell lines, namely promyelocytic leukemia HL-60 and histiocytic lymphoma U-937, revealed its cytotoxicity greater than that of hydroxyurea and comparable to BCNU used as standards. Its in vivo anti-tumoral potency was assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice. Results revealed significant tumor regression effects in these tumors. The survival time of treated mice was markedly increased by combination of the compound 1 with dopamine hydrochloride. Its toxicity was assessed in vivo in normal and EAC bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularities as well as biochemical parameters sequentially on days 9, 14 and 19 following drug treatment at the optimum dose of 30 mg/kg from day 1 to 7. Results indicated that initial suppression in the femoral bone marrow cellularity seen on day 9 reached normalcy by day 19. Other parameters were within normal limit. Histopathological studies of liver revealed mild hepatotoxicity on day 9 in treated groups that substantially recovered on day 19. Similar studies with heart and kidney revealed no cardio toxicity or nephrotoxicity. Compound 1 comparable to standards inhibited the synthesis of DNA and RNA in S-180 tumor cells.

Evaluation of fluorenhymustine as a rationally designed novel anticancer agent.

AIM: To develop a rationally designed new nitrogen mustard namely Fluorenhymustine (compound 2), where N,N'-bis(2chloro-ethyl)amino group, the established anticancer functionality, is attached to the 2-ethyl fluorenone hydantoin moiety. MATERIALS AND METHODS: Starting from fluorenone hydantoin, a 3-step synthetic procedure was followed to obtain the title compound. 4-(4-Nitrobenzyl)pyridine was used to assess its chemical alkylating activity. Murine tumors (Ehrlich ascites carcinoma (EAC) and Sarcoma-180 (S-180)) were used to assess its in vivo activity. Its cytotoxicity was determined in vitro in MCF-7 human breast tumor cell line, toxicity - in vivo in normal and EAC bearing mice. 3H-Thymidine and 3H-Uridine were employed to study its inhibitory effect on DNA and RNA synthesis respectively in S-180 tumor cells in vitro. RESULTS: Alkylating activity of fluorenmustine exceeded that of N-di(2-chloroethyl)amine used as a standard alkylating compound. It has displayed an excellent and reproducible antitumor activity in vivo against EAC and S-180 comparable to that of 5-fluorouracil judging by the increase in median survival times of treated animals. It also significantly increased the life span of mice bearing advanced tumors for 6 days before the drug challenge. However in vitro screening in MCF-7 did not reveal any significant cytotoxicity. The compound did not adversely affect hematopoiesis at its optimum dose. Drug-induced hepatotoxicity and nephrotoxicity were also not detected. It inhibited the synthesis of DNA and RNA in S-180 tumor cells at 8 microM concentration. CONCLUSION: Results indicated promising chemotherapeutic potential of Fluorenhymustine.

Evaluation of naphthal-NU, a 2-chloroethylnitrosourea derivative of naphthalimide, as a mixed-function anticancer agent.

Naphthal-NU, 2-[2-[3-(2-chloroethyl)-3-nitrosoureido]ethyl]-1H-benz[de]isoquinoline-1,3-dione (Compound 1) has been synthesized as a rationally designed new mixed-function anticancer agent from 1,8-naphthalic anhydride. Its chemical alkylating activity compared with CCNU as standard compound indicated that it possesses greater alkylating activity than the latter. Its antitumour efficacy was assessed in vivo in two murine ascites tumours namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. Three clinical drugs namely CCNU (lomustine), endoxan (cyclophosphamide) and 5-fluorouracil (5-FU) were used as positive controls for comparison. Compound 1 has displayed excellent and reproducible antitumoural activity having curative effects in these tumours comparable with CCNU and 5-FU. It has also significantly increased the life span of mice bearing highly advanced tumour for 10 days before the drug challenge. Its toxicity was also assessed in vivo in normal and in S-180 bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 50 mg/kg from day 1 to 7. The results indicated that the compound did not adversely affect hematopoiesis. Drug-induced hepatotoxicity and nephrotoxicity were also evaluated at its optimum dose on those days but no such toxicities were detected. It was further screened in vitro in 6 different human tumour cell lines but no significant activity was observed in those lines.

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.

Influence of dietary restriction and soyabean supplementation on the growth of a murine lymphoma and host immune function.

A comparative study was made to reveal the influence of caloric restriction with or without soyabean in the diet on the growth of a murine lymphoma, host survival, serum profile of vitamin A and E and immune status of the host. Caloric restriction delayed and inhibited tumour growth and improved host survival; inclusion of soyabean during restriction enhanced this effect. Dietary restriction both in the absence and presence of soyabean improved the proliferative response of peripheral blood lymphocytes. This was accompanied by increased cytolytic activity of peritoneal macrophages and elevation in serum immunoglobulins (IgG and IgM). Levels of vitamins A and E, which is found to be low in tumour bearing animals, decreased further when maintained in the restricted diet without soyabean, but was raised to normal levels following addition of soyabean in the diet. These observations imply that tumour growth is arrested possibly by insufficient nutrition available due to dietary restriction, for actively proliferating tumour cells and by improvement in host immune mechanism in the presence of soyabean in the diet.

Evaluation of phthalmustine, a new anticancer compound. I. Effect on Dalton's ascitic lymphoma in mice.

The anticancer property of phthalmustine, a hitherto unknown compound containing N-mustard attached to the phthalimide ethyl chain was evaluated using a murine tumor model. The results indicate that the compound was effective in significantly restraining tumor growth. This was accompanied by marked improvement in host survival. No toxic reactions were apparent as reflected in skin and hair texture, body weight and behavioral pattern (food and water intake and activity). Blood picture showed a shift towards the normal following treatment. DNA synthesis in tumor cells was found to be affected as revealed by radioactive thymidine incorporation.

Vitamin E--its status and role in leukemia and lymphoma.

A comparative study has been performed on the relationship between vitamin E and immunofunction in normal and malignant condition in human and murine systems. Further, the effects of supplemental vitamin E on tumor take, host survival and tumor growth have been studied in a transplantable lymphoma in mice. Vitamin E was assayed in serum samples from normal subjects and from patients with leukemia and lymphoma by high performance liquid chromatography (HPLC). The murine group included Dalton's ascitic lymphoma (DL), Schwartz lymphoblastic leukemia (SVL) and Moloney lymphoblastic leukemia (MVL). Serum vitamin E was found to be lower than that of the normal controls in all cases of leukemia and lymphoma both in human and animal system. The levels of immunoglobulins (IgG and IgM) were found to be higher in mice with leukemia and lymphoma. Supplementary vitamin E administered at the initial phase of development of murine lymphomas reduced the rate of tumor growth, improved host survival and elevated serum vitamin E level. Vitamin E supplementation also activated specific mitogen induced blastogenesis of peripheral blood lymphocytes (PBL) and elevated serum IgG level. IgM remained unaltered and macrophage activity did not seem to be affected. The present findings indicated a low status of vitamin E in tumor bearing host and a beneficial effect of supplemental vitamin E on the host which was mediated by the host immune system.

Alkylphosphonium salts as a new class of antitumor agents.

A series of twenty-four alkylphosphonium salts were prepared and evaluated as potential antitumor agents in vivo against Ehrlich ascites carcinoma (EAC). Eleven compounds were screened in vivo against lymphoid leukemia L1210 and one against lymphocytic leukemia P388. Out of these, three compounds exhibited mild antitumor activity against EAC. Twenty compounds were tested for their cytotoxic activity against the growth of tissue culture cells originated from human epidermoid carcinoma of the nasopharynx (KB). All compounds but one exhibited significant cytotoxicity in this cell line. 2-Bromoethyltriphenylphosphonium bromide, chosen as a standard compound, was earlier reported [4] to have borderline activity against P388, but it failed to show any activity against EAC though it has exhibited significant in vitro cytotoxicity in KB cell culture. In the course of this study, seven new alkylphosphonium salts were synthesized.