The growth and metastatic behavior of several human tumor lines grown in adult nude mice, nude mice pretreated with antiserum against asialo GM1 glycoprotein, and beige nude mice were studied. The cell lines were all injected s.c. and i.v. A human colon carcinoma line was also injected into the spleen, and two human renal carcinoma lines were injected into renal subcapsule. All the tumor lines grew as fast or faster in adult nude mice compared with beige nude mice. There were no discernible differences in the production of experimental lung metastasis among the three groups of mice, but human colorectal carcinoma cells and human renal carcinoma cells produced more metastases in nude mice than in beige nude mice after intrasplenic or renal subcapsule injection, respectively. In vitro cytotoxicity assays confirmed that adult nude mice had high levels of natural killer (NK) cell activity whereas nude mice pretreated with anti-asialo GM1 serum and beige nude mice did not. The in vitro NK cell activity of nude mice was demonstrable against mouse lymphoma cells but not against human leukemia cells which were sensitive to lysis by human NK cells. These results suggest that the implantation of human tumor cells into beige nude mice, which are deficient in NK cell activity does not provide an advantageous model for the study of growth and metastasis of human neoplasms.

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In vivo selection of human renal cell carcinoma cells with high metastatic potential in nude mice.

Studies were made to determine whether the orthotopic implantation of human renal cell carcinoma cells (HRCC) into nude mice will produce distant metastases, thus allowing for the selection of variant cells with high metastatic potential. The parental SN12C line was established in culture from a surgical specimen of HRCC. The renal subcapsule (RSC) of adult nude mice was injected with SN12C cells; the mice were killed when they became moribund. Cell lines were established from either single or multiple lung HRCC metastases. The intravenous injection of many (but not all) of the metastasis-derived lines produced significantly more experimental metastases than did the parental cells. The injection of cells into the RSC demonstrated that, in general, cells derived from spontaneous metastases were more metastatic than cells of the parental line. Hence adult nude mice can be used to select HRCC cells with high metastatic potential. These HRCC variant lines offer a good model for studying the cell properties of metastatic HRCC.

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Convulsions after clomiphene citrate.

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Evolution of chemotherapy with platinum compounds.

Cancer is a major disease entity and cause of death in the human population. The discovery of cisplatin has revolutionized the chemotherapy of human cancer. The full therapeutic potential of cisplatin has not been realized due to the serious side effects and emergence of cisplatin-resistant tumor cells associated with its usage. Protective methods such as extensive hydration, improved schedules of administration, alternate routes of administration, and use of protective agents against specific side effects have allowed the use of higher doses of cisplatin against cisplatin-resistant tumors and has extended the list of tumor systems responsive to cisplatin chemotherapy. Incorporation of cisplatin into a number of cisplatin-based anti-cancer drug combinations has enhanced its effectiveness and allowed the use of lower doses of cisplatin, thus reducing its toxic side effects. Finally, the availability of cisplatin analogues, such as carboplatin and others with reduced toxicity, but increased effectiveness against cisplatin-resistant tumors, has expanded the potential scope and therapeutic promise of the platinum anti-cancer agents. The evolution of chemotherapy with the platinum antitumor compounds is ongoing.

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Evidence for metastatic heterogeneity of human renal cell carcinoma.

We determined whether human renal cell carcinoma (HRCC) is heterogeneous and contains cells with different metastatic properties. The parental SN12C line was established in culture from a surgical specimen of HRCC. Clonal populations of cells were isolated by a double-dilution technique. Cells from parental and 11 clonal lines were injected subcutaneously, intravenously, and into the renal subcapsule of nude mice. Seven of the 11 cloned lines differed significantly from the parent line in their ability to produce pulmonary metastases after renal subcapsule injection. These results indicate that this HRCC is heterogeneous for metastasis, and that the outcome of metastasis in nude mice is influenced by the site of implantation.

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Hereditary hemochromatosis.

Genetic (hereditary) hemochromatosis is probably the most common autosomal recessive disorder found in white Americans, of whom about 5/1,000 (0.5 percent) are homozygous for the associated gene. The hemochromatosis gene is probably located close to the HLA-A locus on the short arm of chromosome 6. Homozygous individuals may develop severe and potentially lethal hemochromatosis, especially after age 39. Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body. Excess iron storage eventually produces pituitary, pancreatic, cardiac, and liver dysfunction and death may result from cardiac arrhythmias, congestive heart failure, and/or hepatic failure or cancer. Early diagnosis can prevent these excess iron-induced problems. Iron overload owing to HLA-linked hereditary hemochromatosis can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations. Patients at risk for genetic hemochromatosis should be screened, identified, and treated as early as age 20 to prevent or minimize the deadly complications of hemochromatosis. Population screening should include measurements of serum iron concentration, total iron binding capacity (TIBC), percent saturation of transferrin, and serum ferritin concentrations. Family members of hereditary hemochromatosis patients are at increased risk and should be tested. Screening, identification and early treatment (phlebotomies, sometimes in combination with the use of Desferal or other iron-chelating agents) may help prevent or reduce iron-related organ damage and premature deaths. Early diagnosis and treatment will reduce the population of aging individuals with severe, complicated hemochromatosis and dramatically reduce medical costs (billions of U.S. dollars per annum) associated with the management of this disease.

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