title: Tumor regression and induction of anti-tumor immunity by local chemotherapy of guinea-pigs bearing a line-10 hepatocarcinoma.
abstract: Local administration of a low dosage of the active cyclophosphamide derivative 4-hydroperoxy-cyclophosphamide (4-HPCY) at the site of antigenic stimulation strongly enhances T-cell-mediated immune responses in both mice and guinea-pigs. Such immunopotentiation is related to functional elimination of suppressor cells from the draining lymph nodes. In the present study we examined the potential immunotherapeutic effects of local cytostatic drug administration in strain-2 guinea-pigs bearing a line-10 hepatocarcinoma. This tumor, when injected intradermally (10(6) cells) metastasizes within 7 days into the draining lymph node and untreated animals die within 60-80 days from metastatic growth. In sensitization experiments, using irradiated line-10 tumor cells, potentiation of delayed-type hypersensitivity reactivity was observed with local administration of low dosages of 4-HPCY. Intralesional treatment with increasing dosages of 4-HPCY, when started 7 days after tumor-cell inoculation and continued for 3 weeks, resulted in a dose-dependent regression of the primary tumor. Cure rates of up to 75% were achieved. All cured animals showed strong delayed-type hypersensitivity reactivity towards line-10 cells and were resistant to a rechallenge with 10(6) line-10 tumor cells. When treatment was started at a very late stage of the disease (day 14) only a small number of animals were cured. However, when local chemotherapy was preceded by one (non-curative) systemic dose of cyclophosphamide, a 57% cure rate was obtained. Again, all cured animals showed strong delayed-type hypersensitivity reactivity and protective immunity to line-10 tumor cells. Tumor immunity was transferable to naive recipients with immune spleen cells and was T-cell-dependent. Other cytostatic drugs, selected for local immunopotentiating capacity, notably etoposide (VP16) and cis-platinum (cis-Pt) were similarly effective in the local chemotherapy protocol.
authors.affiliation: Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Claessen
authors.forename: H
authors.initials: H
authors.lastname: Valster
authors.forename: H
authors.initials: H
authors.lastname: Bril
authors.forename: P A
authors.initials: PA
authors.lastname: Steerenberg
authors.forename: B T
authors.initials: BT
authors.lastname: Tan
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006168:Guinea Pigs; D006968:Hypersensitivity, Delayed; D016219:Immunotherapy, Adoptive; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D005047:Etoposide; D003520:Cyclophosphamide; C011272:perfosfamide