T-CELL RECONSTITUTION BY MOLECULAR, PHENOTYPIC, AND FUNCTIONAL-ANALYSIS IN THE THYMUS, BONE-MARROW, SPLEEN, AND BLOOD FOLLOWING SPLIT-DOSE POLYCHEMOTHERAPY AND THERAPEUTIC ACTIVITY FOR METASTATIC BREAST-CANCERIN MICE

We examined the effect of a maximum tolerated, split-dose chemotherapy protocol of cyclophosphamide, cisplatin, and 1,3-bis (2-chloroethyl)1 1-nitrosourea (BCNU) on neutrophil and lymphocyte subpopulations in th e peripheral blood leukocytes (PBLs), thymus, bone marrow, and spleen. It was found that this protocol of polychemotherapy, modeled after th e induction protocol used with autologous bone marrow transplantation (AuBMT) for breast cancer, suppressed both B- and T-cell populations a nd T-cell function at times when the absolute neutrophil count had ret urned to normal or supernormal numbers. We observed an organ- and phen otype-specific T- and B-cell recovery to normal levels following chemo therapy. However, despite normalization of cellularity and phenotype f requency, splenic lymphocytes remained unable to respond to normally c oncanavalin A (ConA). This polychemotherapy protocol in mice with an e xtensive experimental metastasis mammary tumor burden, was a dose leth al to 20% of the test group, which could be overcome with treatment by BMT and rHu interleukin (IL)-7. Furthermore, therapy with the T-cell augmenting agent rHu IL-7 had additive therapeutic activity and signif icantly prolonged survival beyond that of chemotherapy and BMT althoug h it did not cure any mice with a heavy tumor burden. In summary, thes e studies demonstrate an organ-specific and selective polymorphonuclea r neutrophil and T- and B-cell reconstitution following multidrug, spl it-dose chemotherapy on tissue and PBL populations, and a chronic depr ession in T-cell function, which when modified can result in significa nt therapeutic activity.