Repeated observations in our laboratory show that 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 sc 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 weeks 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 with 7 (+/- 1.5) nodules. This amplifying effect was found
after treatment with two 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
nickel-induced soft tissue
tumor. Several hypotheses have been proposed. 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 cells, for example, could be possible. Alternatively, a direct effect of the
drug on lung tissue, especially 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 we 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, our study shows a possible risk in the use of these drugs for inductive or
adjuvant chemotherapy.