Renal, hepatic, cardiac and thymic acute toxicity afforded by bis(helenalinyl)malonate in BDF1 mice.
Bis(helenalinyl)malonate [BHM], a pharmacologically active sesquiterpene lactone potentially useful as an antineoplastic agent, proved to be less toxic than its parent compound, helenalin. Its LD50 in BDF1 mice, i.p. was more than twice that of helenalin. Its lower toxicity allowed a higher therapeutic dose (15 mg/kg/day vs. 8 mg/kg/day for helenalin) which, in turn, afforded a greater T/C% (261 vs. 161). When BHM was employed at its therapeutic dose of 15 mg/kg/day, no marked toxicity was evident after three daily doses. However, continuation of treatment at this level led to both kidney and liver toxicity as measured by clinical chemistry parameters. Histological lesions in the thymus and kidney were demonstrated within 48 h at 25 mg/kg as a single dose. Apparently the toxicity was delayed with BHM but accumulated over time. Transient cardiotoxicity occurred with the drug and the agent was suspected of causing intestinal blockage.
Hall
I H
IH
Department of Biochemistry, University of North Carolina, Chapel Hill 27599.
Grippo
A A
AA
Holbrook
D J
DJ
Chang
J J
JJ
Yang
L M
LM
Chaney
S G
SG
Lee
K H
KH
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D012717:Sesquiterpenes / Q000633:toxicity; D045789:Sesquiterpenes, Guaiane; D013729:Terpenes / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D013729:Terpenes; C001329:helenalin; C037387:bis(helenalinyl)malonate