Lack of response to multiple genotoxic agents at the hprt locus in peripheral blood T-lymphocytes of cynomolgus monkeys.
We tested the ability of a series of known genotoxic agents to cause mutations at the hprt locus in peripheral blood T-lymphocytes of cynomolgus monkeys as measured by the ability to form clones in the presence of 6-thioguanine. Ethylmethane sulfonate (EMS, 300 mg/kg i.p.), chloroethylmethane sulfonate (CI-EMS, 35 or 50 mg/kg i.p.), and the Pharmacia & Upjohn antitumor agents adozelesin (1.6, 4, 6, or 8 microg/kg i.v.) and CC-1065 (6 microg/kg i.v.) were all negative in the hprt mutation test. Results with cyclophosphamide (CP, 75 mg/kg i.v.) were equivocal. Adozelesin, CC-1065, and CI-EMS treatments increased the percentage of T-lymphocytes with chromosome aberrations, as well as inducing types of aberrations not seen in control cells. EMS and CP were not tested for chromosome aberrations. We have previously shown that treatment of monkeys with 77 mg/kg ENU substantially increased the hprt mutant frequency, with a lag time of approximately 77 days between treatment and peak MF values. The results of the present study suggest a low sensitivity of the hprt mutation assay to certain classes of genotoxic agents in cynomolgus monkeys.
Zimmer
D M
DM
Investigative Toxicology Unit, Pharmacia & Upjohn Co., Kalamazoo, Michigan 49001, USA.
Harbach
P R
PR
Mattano
S S
SS
Yu
R L
RL
Mattes
W B
WB
Aaron
C S
CS
D000818:Animals; D001572:Benzofurans; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D003509:Cyclohexanecarboxylic Acids / Q000633:toxicity; D053138:Cyclohexenes; D003520:Cyclophosphamide / Q000633:toxicity; D000080890:Duocarmycins; D005020:Ethyl Methanesulfonate / Q000031:analogs & derivatives / Q000633:toxicity; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D007211:Indoles; D007933:Leucomycins / Q000633:toxicity; D008252:Macaca fascicularis; D009153:Mutagens / Q000633:toxicity*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology
D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D009153:Mutagens; C018782:CC 1065; C060090:adozelesin; D003520:Cyclophosphamide; D005020:Ethyl Methanesulfonate; D007041:Hypoxanthine Phosphoribosyltransferase