Antitumor and antimetastatic effects of dacarbazine combined with cyclophosphamide and interleukin-2 in Lewis lung carcinoma (3LL).
The antitumor and antimetastatic activity of dacarbazine (DTIC) alone or in combination with cyclophosphamide (CY) was tested in C57BL/6 mice bearing Lewis lung carcinoma (3LL). Treatment with both agents significantly reduced tumor growth and the number of metastases. These effects were associated with marked changes of the biochemical and immunological properties of drug-treated 3LL cells, i.e. (a) reduction of alpha 6 integrin expression, (b) increased susceptibility to natural immunity in vivo, as measured in terms of rapid clearance from mouse lungs of prelabeled 3LL cells injected i.v. and (c) increased immunogenicity, as assessed by T-cell-mediated immune responses (i.e. graft rejection by intact syngeneic mice, and frequency of specific CTL precursors recognizing DTIC/CY-treated cancer cells). The immunotherapeutic advantage afforded by increased immunosensitivity and immunogenicity of 3LL cells exposed to DTIC + CY appears to be markedly reduced in vivo by the profound immunodepressive effects of these drugs. Within this context, addition of interleukin-2 was found to increase the antitumor and antimetastatic activity of this chemotherapeutic regimen. The present study shows, for the first time in a solid tumor model, that a biological response modifier increases the antitumor efficacy of drugs that are able to affect the immunological properties of cancer cells.
Tentori
L
L
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
Leonetti
C
C
Lozupone
F
F
Bonmassar
E
E
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000556:secondary / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000494:pharmacology; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D039503:Integrin alpha6; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
D015703:Antigens, CD; D018906:Antineoplastic Agents, Alkylating; D007155:Immunologic Factors; D039503:Integrin alpha6; D007376:Interleukin-2; D009363:Neoplasm Proteins; D003606:Dacarbazine; D003520:Cyclophosphamide