Increasing therapeutic effect and reducing toxicity of doxorubicin by N-acyl dehydroalanines.
Doxorubicin toxicity is generally accepted to be free radical-mediated. N-Substituted dehydroalanines (indexed as AD compounds) are capto-dative olefins which react and scavenge free radicals, especially the superoxide anion (O2-) and hydroxyl radical (HO). AD-20, an orthomethoxyphenylacetyl dehydroalanine derivative, decreases the mortality of mice when administered before an acute single dose or multiple non-toxic doses of doxorubicin. Doxorubicin administered to mice induces elevated serum transaminase levels, and the pretreatment of mice with AD-20 decreases significantly these serum enzymatic activities. Preliminary histological examinations suggest that these serum transaminase elevations reflect most likely liver injury. In addition to its cardiotoxicity, doxorubicin induces a severe bone marrow depletion. Although this initial decrease in the peripheral leukocytes induced by doxorubicin is not prevented by the administration of AD-20, it produces a fast recuperation in the white blood cells levels after 1 week, supporting a protective effect at this level. Moreover, the antitumor effect of doxorubicin in L1210 tumor-bearing mice was enhanced when AD-20 was injected before doxorubicin. We postulate that these effects may be related to the free radical scavenging ability of AD-20.
Buc-Calderon
P
P
Unité de Biochimie Toxicologique et Cancérologique, Ecole de Pharmacie, Université Catholique de Louvain, Belgium.
Praet
M
M
Ruysschaert
J M
JM
Roberfroid
M
M
D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001853:Bone Marrow / Q000187:drug effects; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity*; D007939:Leukemia L1210 / Q000188:drug therapy*; D008297:Male; D051379:Mice
C053274:AD 20; D004317:Doxorubicin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000409:Alanine