Extent of Damage and Repair in the p53 Tumor-Suppressor Gene After Treatment of Myeloma Patients With High-Dose Melphalan and Autologous Blood Stem-Cell Transplantation Is Individualized and May Predict Clinical Outcome

Abstract

Purpose To quantitate the individual levels of melphalan-induced DNA damage formation and repair in vivo and to search for possible correlations with clinical outcome in patients with multiple myeloma (MM). Patients and Methods The formation and subsequent repair of DNA damage (monoadducts and interstrand cross-links) in the p53 tumor-suppressor gene, the proto-oncogene N-ras, and the housekeeping gene beta-actin during the first 24 hours after treatment with high-dose melphalan (HDM; 200 mg/m2) supported by autologous blood stem-cell transplantation (ABSCT) was measured in blood leukocytes of 26 patients with MM. The peak DNA adduct levels, the total amount of adducts over time, and the rate of adducts repair in each gene were correlated with response and time to progression after HDM. Results The levels of gene-specific DNA damage formation and the individual repairing capacity varied up to 16-fold among patients, indicating that the melphalan-induced biologic effect in vivo is highly individualized. A significantly greater DNA damage and a slower rate of repair in p53 for all end points under study were found in patients who achieved tumor reduction compared with nonresponding patients. Furthermore, longer progression-free survival correlated with increased peak monoadduct levels in the p53 gene (P = .032). Conclusion Increased DNA damage and slower repairing capacity in the p53 gene from blood leukocytes after HDM correlate with improved outcome of patients with MM who undergo ABSCT. These results suggest that quantitation of such biologic end points may identify patients who are more likely to benefit from this procedure.