Evaluation of the Use of DNA Adduct Dosimetry to Optimize the Timing of High Dose Therapy for Breast Cancer

摘要

For drugs that interact with DNA, measures of DNA damage can assess the intracellular availability of active drug at a critical molecular target. Measurements of DNA damage should reflect the integrated effect of all resistance factors, including both recognized mechanisms and uncharacterized mechanisms. Thus, molecular measures of DNA damage could provide an important tool for elucidating the time course of complex changes in resistance factors. Motivated by a recent clinical trial that demonstrated better survival when the interval between induction chemotherapy and high dose therapy was prolonged, this project is using measures of DNA damage to determine whether induction chemotherapy causes transient changes in resistance. Findings indicate cyclophosphamide, cis-platin, and BCNU each produce DNA damage that an be measured in a dose dependent manner. Using a laser scanning cytometer, individual cells can be identified on slides. The characteristics of the individual cells (e.g., the presence of markers for normal or cancer cells) and cytoplasmic features (e.g. markers for apoptosis or enzymatic or other factors associated with resistance to chemotherapy) can be characterized by immunohistochemistry. Assays for DNA damage can be conducted in the same cells and associations between DNA damage and cytoplasmic features determined at the individual cell level.