DNA adduct dosimetry and DNA repair in rats and pigs given repeated doses of procarbazine under conditions of carcinogenicity and human cancer chemotherapy respectively.
Procarbazine (PCZ), an antineoplastic agent that produces methylated bases in DNA after metabolic activation, has been implicated in the development of secondary cancers in patients treated for a primary neoplasm. The repair of the important promutagenic lesion, O6-methylguanine (O6-meG) by O6-alkylguanine-DNA alkyl transferase (AGT) is believed to be crucial for the stability of O6-meG and for the tumorigenic outcome after exposure to methylating carcinogens. Using two different animal models, we investigated methyl DNA adduct dosimetry and DNA repair in (i) female rats given repeated doses of PCZ for 20 weeks under conditions of carcinogenicity, and (ii) female pigs administered repeated doses of PCZ for 4 weeks according to a regimen comparable to that given to human subjects undergoing cancer chemotherapy. After each successive week, four rats and three pigs were killed and tissues including blood, liver, mammary gland, spleen, thymus and lymph node were taken. The levels of O6-meG, 7-methylguanine (7-meG) in DNA and of AGT were determined in these tissues. In the rat, O6-meG in the liver DNA, and to a lesser degree in the spleen was efficiently removed throughout the 20 week dosing period, as indicated by the O6-meG/7-meG ratio being much less than 0.11. In the target organs, accumulation of O6-meG began in the mammary gland after 9 weeks, and in the lymph node and thymus after 3 weeks of dosing. Interestingly, the accumulation of O6-meG in the mammary gland correlates well with a concomitant decrease in AGT level as from week 10 and may be related to the induction of mammary gland tumors, first detected in two animals at week 10. In pigs, after a total dose of 750-4000 mg of PCZ, the range of 7-meG detected in leukocyte DNA was 21-66 mumol/mol G, which compares well with recent findings in cancer patients treated with PCZ. Similar levels of 7-meG were detected in the pig liver, thymus and lymph node. O6-MeG was only detectable in leukocyte DNA at week 4 with our present method. Compared with control pig tissues, a depressed AGT level was found in the leukocyte, lymph node and brain of the treated animals.
Fong
L Y
LY
Jefferson Cancer Institute, Department of Pharmacology, Thomas Jefferson University, Philadelphia, PA 19107.
Bevill
R F
RF
Thurmon
J C
JC
Magee
P N
PN
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D008780:Methyltransferases / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011344:Procarbazine / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013552:Swine
D011344:Procarbazine; D006147:Guanine; C008450:7-methylguanine; D004247:DNA; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase