Immunotoxicologic effects of cyclosporine on tumor progression in models of squamous cell carcinoma and B-cell lymphoma in C3H mice.
Many immunosuppressive drugs are associated with an increased risk of neoplasia, principally non-melanoma skin cancers and B-cell lymphomas. However, only 6 of the 13 immunosuppressive drugs tested in 2 year bioassays increased the incidence of neoplasia. For example, the 2-year bioassays conducted with cyclosporine (CSA), an International Agency for Research on Cancer (IARC) Group 1 human carcinogen, were negative. The purpose of these investigations was to use transplanted tumor models in immunocompetent, syngeneic mice to gain insight into the failure of the 2-year bioassay to show an increased incidence of neoplasia with CSA. C3H HeN mice were used in a battery of assays with a transplanted squamous cell carcinoma (SCC VII cells) or a B-cell, lymphoma (38C13 cells) cells to study effects of CSA on local growth and metastases, experimental metastases, and progression of established metastases. Mice received CSA twice weekly by subcutaneous (SC) injection at doses of 0.5, 5, or 50 mg/kg; controls received the CSA vehicle. CSA had a modest inhibitory effect on SC tumors initiated by 38C13 cells and on intramuscular tumors initiated by SCC VII cells. CSA also decreased the number of lung colonies and decreased the size, growth fraction and vascularity of established lung metastases initiated by SCC VII cells. In contrast, CSA increased progressive growth of metastases to the sentinel lymph node from an intramuscular SCC VII tumor, but had no effect cellular traffic to the node. In conclusion, CSA at doses up to 50 mg/kg did not facilitate tumor progression and it partially inhibited tumor growth, suggesting that suppression of tumor progression may partially explain the failure of CSA to act as a carcinogen in 2 year bioassays.
Biologics Toxicology, Centocor R&D, Radnor, PA 19087, USA. praffert@its.jnj.com
Patricia
P
Rafferty
Devon
D
Egenolf
Kerry
K
Brosnan
Dorie
D
Makropoulos
Jarrat
J
Jordan
Kay
K
Meshaw
Mindi
M
Walker
Amy
A
Volk
Peter J
PJ
Bugelski
D000818:Animals; D015197:Carcinogenicity Tests; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage / Q000633:toxicity*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007279:Injections, Subcutaneous; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D008207:Lymphatic Metastasis; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008809:Mice, Inbred C3H; D019042:Muscle Neoplasms / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D009361:Neoplasm Invasiveness; D018570:Risk Assessment; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
D007166:Immunosuppressive Agents; D016572:Cyclosporine