PEG-IL-2 therapy of advanced cancer in the guinea pig. Impact of the primary tumor and beneficial effect of cyclophosphamide.
The efficacy of tumor therapy using polyethylene-glycol-modified interleukin-2 (PEG-IL-2), alone or in combination with cyclophosphamide, was studied in advanced metastatic disease in the guinea pig. Line 10 (L10) tumor cells appeared in the axillary lymph node only 7 days after intradermal tumor-cell inoculation, and lymph-node leukocytes were almost completely replaced by tumor cells on day 28. Local treatment of the 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 only some (2 out of 5 cured) of the treated animals. Anti-tumor effects against the primary tumor and against lymph-node metastases were observed only after intratumoral (i.t.) administration of PEG-IL-2. Injection of the agent into or near lymph-node metastases in the absence of the primary tumor had no curative effect. In PBS/BSA-treated control animals the primary tumor and metastases grew progressively. In the treatment of far advanced metastatic disease, the combination of i.t. administration of PEG-IL-2 and i.p. injection of cyclophosphamide (Cy) resulted in improved anti-tumoral effects (5/5 guinea pigs were cured) when compared with monotherapy using either agent (one and none out of 5 animals cured, respectively). PBS/BSA heated controls showed progressive 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 therapeutic effect. Combination of PEG-IL-2 therapy with systemic injections of Cy significantly improved the curative effects of the treatment of advanced metastatic cancer.
Balemans
L T
LT
Laboratory for Pathology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.
Steerenberg
P A
PA
Koppenhagen
F J
FJ
Kremer
B H
BH
De Mulder
P H
PH
Claessen
A M
AM
Scheper
R J
RJ
Den Otter
W
W
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003052:Cochlear Aqueduct; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D004333:Drug Administration Routes; D005260:Female; D006168:Guinea Pigs; D015552:Injections, Intralesional; D007272:Injections, Intralymphatic; D007376:Interleukin-2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D008207:Lymphatic Metastasis; D009362:Neoplasm Metastasis; D011092:Polyethylene Glycols
D007376:Interleukin-2; C067245:interleukin-2, polyethylene glycol-modified; D011092:Polyethylene Glycols; D003520:Cyclophosphamide