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Persistence of Platinum-Ammine-DNA Adducts in Gonads and Kidneys of Rats and Multiple Tissues from Cancer Patients

Medicine Branch, Division of Cancer Treatment [E. R., S. G-B.], and Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Cancer Etiology [M. C. P.], National Cancer Institute; Office of Clinical Director, National Institute of Neurological Diseases and Stroke [D. K.]; and Developmental Therapeutics Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases [C. L. L.], NIH, Bethesda, Maryland 20892

The persistence of platinum-DNA adducts was investigated using normal rats as well as tissues from cancer patients receiving either cis-diamminedichloroplatinum(II) (cisplatin) or diamminecyclobutanedicar-boxylatoplatinum(II) (carboplatin) for cancer chemotherapy. These studies used an enzyme-linked immunosorbent assay, established with a rabbit anti-cisplatin-DNA that is specific for intrastrand platinum-DNA adducts. The gonads and kidneys of male and female rats, sites for antitumor activity and toxicity, respectively, were monitored for cisplatin-DNA adduct formation after a single dose of drug and during multiple-dose exposures (once a wk for 3 wk). DNA adducts were measured by enzymelinked immunosorbent assay 4 h and 2, 4, 7, and 14 days after administering a single i.v. injection of 8 mg/kg of cisplatin. Adduct profiles in renal tissues were similar in both males and females with adduct levels increasing between 4 h and 2 days, decreasing between Days 2 and 7, and stable between Days 7 and 14. In both sexes, levels of kidney DNA adduct measured 7 to 14 days after cisplatin injection comprised about 30% of the highest (Day 2) value. In testes and ovaries, adduct removal was complete by 4 days, and 40 to 50% of adducts present at Day 2 persisted until Days 7 and 14. A study of multiple dosing showed that adducts in renal and testicular DNA from rats given three weekly doses of 5 mg/kg of cisplatin had different accumulation profiles. In the testis there was a 2-fold accumulation of adduct after the third dose, while in the kidney adducts dropped with repeated dosing. In humans, the persistence of platinum-DNA adducts was studied in tissues from eight cancer patients who received their last dose of cisplatin or carboplatin chemotherapy between 1 day and 15 mo before autopsy. The patients had either ovarian cancer, breast cancer, or lymphoma, and the tissues studied included ovarian tumor, bone marrow, kidney, liver, spleen, lymph node, peripheral nerve, and brain. When samples were available from tumor tissues and from bone marrow within the same patient, adduct levels were similar in the two tissues. In addition, adducts were persistent for many months, since half of the individuals received their most recent platinum-drug therapy 7 to 15 mo before death. Overall, these studies demonstrate a widespread distribution and high degree of platinum-DNA adduct persistence in both animal and human tissues subsequent to cisplatin or carboplatin treatment.

¹ To whom requests from reprints should be addressed, at National Cancer Institute, Bldg. 37, Room 3B25, NIH, Bethesda, MD 20892.

Received 7/19/91. Accepted 10/21/91.

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