AMPLIFIED PULMONARY METASTASES OF A RAT RHABDOMYOSARCOMA IN RESPONSE TO NITROSOUREA TREATMENT

  • 1 January 1984
    • journal article
    • research article
    • Vol. 68  (5) , 749-758
Abstract
The chloroethylnitrosourea of cysteamine (CNCC) induces slowed tumor growth rate and decreased lymph node metastasis in rats bearing a rhabdomyosarcoma but concomitantly enhances metastatic dissemination in the lung. Tumors obtained by s.c. graft of tumor cells, in syngeneic rats, gave a reproducible pattern of metastases at nodal and pulmonary sites after a 60-80-day period. CNCC was administered orally at a dose of 50 mg/kg once a week for 5 wk beginning at the time of tumor appearance. Forty-five of 46 CNCC-treated rats had lung metastases with 95 (.+-. 9.7) nodules; in the control group 29 of 41 rats had lung metastases wioth 7 (.+-. 1.5) nodules. This amplifying effect was found after treatment with 2 other nitrosoureas (chlorozotocin and hydroxyethylchloroethylnitrosourea) but not with cyclophosphamide and methotrexate. Lung metastatic amplification was also observed after treatment of the 13762 mammary adenocarcinoma in Fischer rats and treatment of N-induced soft tissue tumor. The dissociated effect of nitrosourea on local tumor, lymph nodes, and pulmonary metastases does not support the concept of systemic immunosuppression as the main mechanism of this phenomenon, but a decrease of local immunological defenses exerted by NK [natural killer] cells, for example, could be possible. Alternatively, a direct effect of the drug on lung tissue, especiallly lesions of endothelial tissue, could be responsible for the observed effect. Nitrosourea treatment of rats after surgical excision of the tumor, as adjuvant chemotherapy, was responsible for an amplification effect in association with local recurrences. From this fact it was hypothesized that nitrosourea treatment could modify the equilibrium of cell subpopulations in the tumor by selecting highly metastatic drug-resistant variants. Although the mechanism of the amplifying effect of nitrosoureas has not been elucidated, this study shows a possible risk in the use of these drugs for inductive or adjuvant chemotherapy.