Therapeutic implications of cell kinetic changes after cyclophosphamide treatment in "spontaneous" and "transplantable" mammary tumors

Abstract

The present studies were initiated to investigate the cell kinetics in spontaneous and transplantable mammary tumors after single doses of cyclophosphamide (Cp). The 3H-thymidine (3H-TdR) labeling index (LI), the DNA synthesis times, and the primer-dependent DNA polymerase labeling index (PDPI) were determined by in vitro methods for spontaneous mammary tumors (SMT) in C3H/HeJ retired breeders and 13762 transplantable rat mammary tumors (RMT) in Fischer 344 rats from 6 hours to 14 days after Cp treatment. The perturbations in the cell kinetics, although quantitatively different in the two tumor models, were qualitatively similar in that transient changes in both PDPI and 3H-TdR LI were observed within the first 24 hours after treatment. These changes were followed by a variable period during which cell proliferation was suppressed. Increases in the PDPI and 3H-TdR LI, presumably reflecting proliferative recovery, were observed prior to the initiation of tumor regrowth. Increases in the 3H-TdR LI and PDPI within the first 24 hours after Cp in C3H/HeJ SMT indicated an interval of increased sensitivity to adriamycin. In the 13762 RMT, combination chemotherapy protocols designed to exploit changes in cell kinetics at early times (24 hours) and during the recovery phase of the response resulted in greater long-term tumor-free survival.