We analyzed mechanisms responsible for organ-specific metastasis by using two melanoma sublines derived from the same mouse tumor, of which one colonizes the lungs (Flo) and the other colonizes the liver (L8) after intravenous injection. Both lines were obtained by selective growth in lung or liver after injection of tumor cells into a tail vein or portal vein. Contrary to common concepts, the cells of the liver-colonizing melanoma line do not accumulate preferentially in the liver after intravenous administration in vivo. However, the selective survival and proliferation of these melanoma cells in the target organ (liver) may be explained by the unexpected observation that they can be specifically stimulated to proliferate in the presence of hepatocytes, whereas the cells of the lung-colonizing line cannot. Growth promotion under coculture conditions in vitro was monitored both by thymidine incorporation into DNA and by increase in cell numbers. The proliferative stimulus is not mediated by an easily diffusible factor but rather depends upon direct contact between liver cells and those tumor cells that metastasize to that particular organ.It is common clinical experience that a malignant primary cancer, although shedding viable cells throughout the body, will only give rise to gross metastases in certain specific tissues (1,2) and that the specific nature of these secondary sites depends upon the histological origin of the primary tumor. Apparently, the host tissue must be able to reciprocate this recognition in some way, if only passively (3).Some progress in explaining the general mechanisms of metastasis has been made recently through the recognition of autocrine motility factors that induce pseudopodia formation and hence exploratory cell migration (4). Earlier advances were made with variant and mutant cells that had different degrees of metastatic ability correlating with cell-surface alterations (5). Later, variants of metastasizing mouse melanoma cells were selected with preference for the liver (6). Fusion of nonmetastatic tumor cells with reticuloendothelial cells can also give rise to metastatic hybrids having distinct site specificities (7).This phenomenon has some interesting analogies with other homing and tissue interaction systems such as the inhibitory regulation of a melanoma by embryonic skin (8), the growth stimulation of neuroblastoma cells by neonatal sympathetic ganglia (9), fetal fat tissue and its supportive interaction with numerous fetal epithelia (10), and the stimulation by human melanoma and carcinomas of fibroblasts to produce hyaluronate (11).We show here that a specific interaction occurs between adult hepatocytes and liver-metastasizing melanoma cells resulting in the stimulation of the proliferation of the tumor cells. MATERIALS AND METHODSIn Vivo Experiments. Organ specificity. An organ-specific mouse melanoma of the F1 line of B16 melanoma cells (from I. J. Fidler, Houston) was isolated by administration into the portal vein, recovery and growth of liver colonies in ...
Clinical observations indicate that individual tumours vary in the extent to which they colonise distant organs and in the distribution of their metastatic deposits after blood-borne dissemination.
The metabolism and pharmacokinetics of carbonyl [14C] labelled ethyl, n-butyl, n-hexyl and n-octyl carbamates has been examined in rats after oral and intravenous administration. Hydrolysis of the carbamate group was a major metabolic fate, particularly of the more water soluble carbamates. Conversely, with increasing lipophilicity increasing amounts of omega-1 oxidation products were found both in plasma and urine. The plasma pharmacokinetic data could not be explained by a simple bi-exponential model, ethyl carbamate in particular showing unexpectedly persistent blood levels. A model has been proposed to explain the pharmacokinetic data for ethyl, n-butyl, n-hexyl and n-octyl carbamates. The essential features of this model are that carbamate is thought not to be in equilibrium between the peripheral and central compartment and that hydrolytic metabolism takes place in the peripheral compartment while oxidative metabolism to urinary metabolites occurs in the central compartment.
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