Immunomodulation by various nitrosoureas and its effect on the survival of the murine host bearing a syngeneic tumor.
Chemotherapeutic efficacies of the nitrosoureas 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), chlorozotocin (CLZ), and streptozotocin (STZ) were investigated against the LSA tumor which is syngeneic to C57BL/6 mice. It was observed that a single injection of 20 mg/kg body weight of BCNU or CLZ, even at an advanced stage of tumor growth, completely cured greater than 90% of the tumor-bearing mice. Furthermore, BCNU-cured or CLZ-cured mice could specifically reject secondary rechallenge with the LSA tumor. In contrast, a single dose treatment with STZ at 20-200 mg/kg body weight failed to cure the tumor-bearing mice (0% survival). The failure of STZ to cure tumor-bearing mice was next addressed considering three possible mechanisms: (a) STZ was less tumoricidal; (b) STZ suppressed the immunity of the host; and (c) STZ failed to eliminate tumor-specific suppressor T-cells. The failure of STZ to cure tumor-bearing mice was not totally related to its tumoricidal properties since STZ at higher doses did possess significant tumoricidal activity in vitro and in vivo, comparable to that of BCNU or CLZ. When spleen cells from normal mice treated with BCNU, CLZ, or STZ were assayed for their responsiveness to the T-cell mitogens concanavalin A or phytohemagglutinin, it was observed that STZ was in fact less immunosuppressive than BCNU or CLZ. The fact that STZ did not suppress the immunity of the host was also suggested by the findings that BCNU-cured mice treated with STZ or CLZ could still reject secondary rechallenge with the specific tumor LSA. Following treatment of tumor-bearing mice with BCNU or CLZ, tumor-specific delayed type hypersensitivity responses were demonstrable in these mice but not in STZ-treated mice. The inability of STZ-treated tumor-bearing mice to elicit a delayed type hypersensitivity response was not due to selective depletion of delayed type hypersensitivity-inducing CD4+ T-cells but was probably due to failure of STZ to eliminate tumor-specific suppressor cells. Together these findings suggested that the failure of STZ to cure LSA tumor-bearing mice was not due to lack of tumoricidal activity or related to suppression of tumor-specific effector T-cell function but may be due to the failure of STZ to eliminate tumor-specific T suppressor cells. The present study suggests that the outcome of chemotherapy with nitrosoureas depends, in addition to the tumoricidal activity of the drug, on the immunomodulating action on the immune mechanisms of the host.
Nagarkatti
M
M
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Toney
D M
DM
Nagarkatti
P S
PS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002330:Carmustine / Q000627:therapeutic use*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007111:Immunity, Cellular; D007167:Immunotherapy; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D013311:Streptozocin / Q000031:analogs & derivatives / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology
C007028:chlorozotocin; D013311:Streptozocin; D002330:Carmustine