The cells of origin of the chemotherapy-curable malignancies are highly sensitive to cytotoxic chemotherapy-mediated cell death

At present, the detailed mechanisms of how cytotoxic chemotherapy routinely produces cure in a limited number of malignancies whilst causing only more modest effects on the majority of cancers and healthy normal cells are uncertain. In this article, we reviewed published information regarding the impact of chemotherapy exposure on the viability of the cells of origin of a number of chemotherapy-curable malignancies. In general, these cells are difficult to study as they are transient, challenging to study ex vivo , and anatomically relatively inaccessible. In B-cell and T-cell acute lymphoblastic leukaemia, it is apparent that exposure to DNA damaging chemotherapy or radiotherapy results in near total loss of the respective cells of origin of pro-B cells and double-positive (DP) thymocytes within 2 days. However, these cells are rapidly replaced from the chemotherapy-resistant bone marrow stem cells. In diffuse large B-cell lymphoma, the germinal centre cells of origin are naturally poised on the edge of apoptosis, with a half-life of approximately 6 h, making in vitro study impractical. The probable cell of origin of testicular cancer is the OCT4 + stem cell, which shows similar sensitivity to chemotherapy to that of malignant cells, with total loss of these stem cells upon exposure to BEP (bleomycin, etoposide, and platinum/cisplatin) combination chemotherapy. Overall, it appears that chemotherapy-curable malignancies do not acquire a high degree of sensitivity to chemotherapy on their change to the malignant phenotype; rather, they maintain the high sensitivity of their cells of origin. These findings are in keeping with our previous observations that the high degree of chemotherapy sensitivity follows the dramatic changes in apoptotic sensitivity that accompany the genetic manipulations of variable–diversity–joining (VDJ) recombination, somatic hypermutation, meiosis, and nuclear fusion occurring in these normal healthy but transient cells.