DRDE-07 and its analogues as promising cytoprotectants to nitrogen mustard (HN-2)--an alkylating anticancer and chemical warfare agent.
Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well as blister inducing chemical warfare agent. We evaluated the cytoprotective efficacy of amifostine, DRDE-07 and their analogues, and other antidotes of mustard agents against HN-2. Administration of 1 LD(50) of HN-2 (20mg/kg) percutaneously, decreased WBC count from 24h onwards. Liver glutathione (GSH) level decreased prominently and the maximum depletion was observed on 7th day post-HN-2 administration. Oxidised glutathione (GSSG) level increased significantly at 24h post-administration and subsequently showed a progressive decrease. Hepatic malondialdehyde (MDA) level and percent DNA damage increased progressively following HN-2 administration. The spleen weight decreased progressively and reached a minimum on 3-4 days with subsequent increase. The antidotes were administered repeatedly for 4 and 8 days after percutaneous administration of single sublethal dose (0.5 and 0.25 LD(50)) of HN-2. Treatment with DRDE-07, DRDE-30 and DRDE-35 significantly protected the changes in spleen weight, WBC count, GSH, GSSG, MDA and DNA damage following HN-2 administration (0.5 and 0.25 LD(50)). There was no alteration in the transaminases (AST and ALT), and alkaline phosphatase (ALP) activities, neither with HN-2 nor with antidotes. The present study shows that HN-2 is highly toxic by percutaneous route and DRDE-07, DRDE-30 and DRDE-35 can partially protect it.
Sharma
Manoj
M
Defence Research and Development Establishment, Jhansi Road, Gwalior, India.
Vijayaraghavan
R
R
Gautam
Anshoo
A
D004999:Amifostine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007928:Lethal Dose 50; D008466:Mechlorethamine / Q000633:toxicity*; D051379:Mice; D008970:Molecular Weight; D009929:Organ Size / Q000187:drug effects; D013329:Structure-Activity Relationship
D000931:Antidotes; D018906:Antineoplastic Agents, Alkylating; D002619:Chemical Warfare Agents; C438646:S-2 (2-aminoethylamino)ethylphenylsulfide; D008466:Mechlorethamine; D004999:Amifostine