DNA adducts in human and patas monkey maternal and fetal tissues induced by platinum drug chemotherapy.
Platinum-DNA adducts in placenta and blood from a woman exposed to 200 mg/m2 of cis-diamminedichloroplatinum(II) (cisplatin) and 300 mg/m2 diamminecyclobutanedicarboxylatoplatinum(II) (carboplatin) for ovarian cancer have been documented by cisplatin-DNA enzyme-linked immunosorbent assay (ELISA) and atomic absorbance spectrometry (AAS). A patas monkey model was used to investigate transplacentally induced cisplatin-DNA damage in fetal tissues. During the last trimester of gestation, 5 patas monkeys were given multiple doses of cisplatin to mimic human ovarian cancer treatment. In spite of careful choice of dose and treatment conditions, cumulative toxicity occurred in monkeys given doses comparable on a mg/m2 basis to those received by the human. A total dose of 12 mg/m2 (0.625 mg/kg body weight), given in the last trimester, supported fetal viability, and multiple tissues, taken by cesarean section, were examined in the fetal monkeys. By cisplatin-DNA ELISA and AAS, maternal tissues from the monkey receiving the highest dose contained approximately twice as much DNA damage as the fetal tissues. A similar relationship was observed when we compared DNA adduct formation in fetal liver and biopsies of liver taken from the monkey dams at cesarean delivery. In all of the monkey pairs studied there were very significant levels of DNA damage in the placenta, and high adduct levels in brains of fetuses that survived treatment. Thus, cisplatin does cross the placenta in the patas monkey. These observations imply that the human fetus, for which the total maternal dose was approximately 5.4 mg platinum drug/kg body weight, may also have sustained some DNA damage.
Shamkhani
H
H
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892.
Anderson
L M
LM
Henderson
C E
CE
Moskal
T J
TJ
Runowicz
C D
CD
Dove
L F
LF
Jones
A B
AB
Chaney
S G
SG
Rice
J M
JM
Poirier
M C
MC
D000328:Adult; D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D002945:Cisplatin / Q000097:blood / Q000378:metabolism*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy; D004247:DNA / Q000097:blood / Q000378:metabolism*; D018736:DNA Adducts; D004797:Enzyme-Linked Immunosorbent Assay; D004901:Erythrocebus patas; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000188:drug therapy*; D013054:Spectrophotometry, Atomic
D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D004247:DNA; D002945:Cisplatin