The potential of platinum-DNA adduct determination in ex vivo treated tumor fragments for the prediction of sensitivity to cisplatin chemotherapy

Background. Response to cisplatin-therapy is assumed to be related to the f ormation of platinum (Pt)-DNA adducts. Measurement of these adducts prior t o therapy could be of value to improve cisplatin based cancer therapy. Materials and methods.. We determined Pt-GG and Pt-AG adduct levels by use of P-32-postlabeling after ex vivo cisplatin treatment of fragments of head and neck squamous cell carcinoma (HNSCC) xenografts (five lines), and of t umor biopsies from patients with HNSCC (n = 8) and testicular cancer (n = 8 ). Results: Adduct levels in fragments (3 x 3 x 3 mm) exposed to 10 to 80 mu M cisplatin for one hour, showed positive correlations with the in vivo resp onse to cisplatin treatment (P < 0.05), as well as with the xenograft adduc t levels observed after in vivo cisplatin treatment (P < 0.02). After an ad ditional five-hour drug-free incubation period the correlations were absent . When patient tumor fragments were exposed ex vivo to 80 mu M cisplatin fo r one hour, adduct levels were similar in HNSCC and testicular cancer. Pers istence of adducts was observed for testicular cancer in the additional dru g-free period. The adduct levels in the samples of two HNSCC patients who r eceived cisplatin chemotherapy were in line with the hypothesis that higher adduct levels are associated with a better response. Conclusion. Our preliminary results show that analysis of DNA adducts follo wing ex vivo drug treatment is a feasible approach towards a predictive ass ay, which warrants further investigation.