title: Locoregional administration of etoposide, but not of interleukin 2, facilitates active specific immunization in guinea pigs with advanced carcinoma.
abstract: Using a guinea pig line 10 hepatocellular carcinoma model for advanced metastatic disease, we studied the therapeutic effect of local cytotoxic drug treatment at the tumor site as compared to, and in combination with, active specific immunization. In addition, locoregional treatment with interleukin 2 (IL-2) was studied. Intratumoral administration of the cytotoxic drug etoposide (VP-16), but not of IL-2, when started in a late stage of tumor growth and continued for 3 wk, caused full regression of all intradermally implanted tumors and cured a small number of animals (14%). When the primary tumor was removed at the onset of treatment, administration of VP-16 and, to a lesser degree, IL-2 at the former tumor site led to improvement of cure rates (up to 30%). Complete cure always coincided with the induction of antitumor immunity. Since both VP-16 and IL-2, when locally administered, strongly augment T-cell-mediated immune responses, the observed therapeutic effect was partially attributed to potentiation of a T-cell-mediated antitumor response. Active specific immunization (ASI) using viable irradiated tumor cells admixed with Bacillus Calmette-Guérin also aims at induction of specific antitumor immunity. In late-stage disease, ASI alone induced cure rates of 39%. Combination of ASI with local cytotoxic drug treatment, but not with locoregional administration of IL-2 at the former primary tumor site, led to very high cure rates (up to 78%). Cured animals were always resistant to a second challenge with line 10 tumor cells. Routinely, one systemic injection with cyclophosphamide was given at the start of all treatment protocols. Omission of CY strongly reduced the cure rates obtained with ASI and locoregional VP-16 treatment. The high cure rates likely relate to the fact that locally administered cytotoxic drugs are capable of reversing immune tolerance, besides exerting direct antitumor action within tumor-draining lymphoid tissues. The present results therefore support our view that local cytotoxic drug treatment should be further explored for its incorporation in antitumor therapies such as ASI, aiming at maximal clinical benefit and minimal toxicities.
authors.affiliation: Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Claessen
authors.forename: E
authors.initials: E
authors.lastname: Bloemena
authors.forename: H
authors.initials: H
authors.lastname: Bril
authors.forename: C J
authors.initials: CJ
authors.lastname: Meijer
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000008:administration & dosage*; D005260:Female; D006168:Guinea Pigs; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D007272:Injections, Intralymphatic; D007376:Interleukin-2 / Q000008:administration & dosage*; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000556:secondary / Q000601:surgery / Q000628:therapy*; D008297:Male; D010081:Oxazolone / Q000276:immunology
chemical_list: D007376:Interleukin-2; D010081:Oxazolone; D005047:Etoposide; D003520:Cyclophosphamide