Evaluation of fluorenhymustine as a rationally designed novel anticancer agent.
OBJECTIVE
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.


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.


CONCLUSIONS
Results indicated promising chemotherapeutic potential of Fluorenhymustine.
Samanta
S
S
Department of Anticancer Drug Development, Chittaranjan National Cancer Institute, Calcutta 700026, India.
Pain
A
A
Ghosh
M
M
Dutta
S
S
Sanyal
U
U
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000494:pharmacology*
D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; C508175:fluorenhymustine