PEG-IL-2 THERAPY OF ADVANCED CANCER IN THE GUINEA-PIG - IMPACT OF THEPRIMARY TUMOR AND BENEFICIAL EFFECT OF CYCLOPHOSPHAMIDE

The efficacy of tumor therapy using polyethylene-glycol-modified inter leukin-2 (PEG-IL-2), alone or in combination with cyclophosphamide, wa s studied in advanced metastatic disease in the guinea pig. Line 10 (L 10) tumor cells appeared in the axillary lymph node only 7 days after intradermal tumor-cell inoculation, and lymph-node leukocytes were alm ost completely replaced by tumor cells on day 28. Local treatment of t he intradermally growing L10 hepatocarcinoma in the guinea pig with a relatively low dose of PEG-IL-2 resulted in regression of the primary tumor and prevention of lymph-node metastases. Therapy was completely curative (4 out of 5 animals) when started on day 7 or 14 after tumor- cell inoculation. When started on day 21, therapy was effective in onl y some (2 out of 5 cured) of the treated animals. Anti-tumor effects a gainst the primary tumor and against lymph-node metastases were observ ed only after intratumoral (i.t.) administration of PEG-IL-2. Injectio n of the agent into or near lymph-node metastases in the absence of th e primary tumor had no curative effect. In PBS-BSA-treated control ani mals the primary tumor and metastases grew progressively. In the treat ment of far advanced metastatic disease, the combination of i.t. admin istration of PEG-IL-2 and i.p. injection of cyclophosphamide (Cy) resu lted in improved anti-tumoral effects (5/5 guinea pigs were cured) whe n compared with monotherapy using either agent (one and none out of 5 animals cured, respectively). PBS/BSA heated controls showed progressi ve tumor-growth. We conclude that large primary tumors and lymph-node metastases can be treated effectively with PEG-IL-2. The i.t. route of administration is of major importance in the treatment of metastases, since administration of PEG-IL-2 near or into the lymph node had no t herapeutic effect. Combination of PEG-IL-2 therapy with systemic injec tions of Cy significantly improved the curative effects of the treatme nt of advanced metastatic cancer. (C) Wiley-Liss, Inc.