The mammalian RPS6 gene, homolog of the Drosophila air8 tumor suppressor gene: is it an oncosuppressor gene?

The mammalian gene encoding the S6 ribosomal protein is the homolog of the Drosophila air8 tumor suppressor gene. We assigned the rat Rps6 gene to chromosome 5q22-33. The rat 5q22-33 chromosome region, previously shown to bear a malignant transformation suppressor gene, is homologous to the human 9p2l region, frequently deleted in various kinds of cancers and also containing at least one tumor suppressor (oncosuppressor) gene. To test the possibility that the Rps6 gene could be an oncosuppressor gene in mammals, we analysed its sequence and expression in normal and malignantly transformed cells. In mouse hepatoma cells (BWTG3), the Rps6 gene is hemizygously deleted but the remaining copy shows no sequence anomaly in the coding region, indicating that Rps6 is not oncosuppressor and that another gene acting as an oncosuppressor is located in its vicinity. In human tumor cells, the RPS6 gene is retained in cells showing deletion of the near-by gene, IFNB. Our results do not support the possibility that the RPS6 gene acts as an oncosuppressor gene in mammalian cells.

A gene for the suppression of anchorage independence is located in rat chromosome 5 bands q22-23, and the rat alpha-interferon locus maps at the same region.

Cell hybrids between malignant mouse hepatoma cells and normal rat fibroblasts with approximately one set of chromosomes from each parent exhibited remarkable karyotypic stability. Most chromosomes of both parents were retained even after prolonged culture in vitro. Normally, such hybrids showed suppression of the transformed phenotype and formed no colonies in soft agar. However, two hybrids, BS140 and BS181, formed a few colonies in soft agar when many cells were seeded, and also occasional foci of cells were detected piling up in monolayer cell cultures. We isolated soft agar colonies (a-subclones) and sub-clones from foci (h-subclones) of both hybrids, and, as a control, subclones of cells from random areas without foci of one hybrid (BS181 p-subclones). When tested for soft agar growth, cells from the a- and h-subclones of both BS140 and BS181 formed colonies at frequencies comparable to the malignant mouse hepatoma parent, whereas the control cells of the BS181 p-subclones (like the normal rat parental cells) yielded no soft agar colonies. All the cell lines were subjected to detailed karyotype analysis in G-banding, which resulted in the finding that cells from the original BS140 hybrid contained at least one copy of each rat chromosome, whereas BS140 a- and h-subclones had lost both copies of rat chromosome 5. Similarly, the original BS181 hybrid contained at least one copy of each rat chromosome, whereas BS181 a- and h-subclones displayed a deletion of the segment q22-23 of rat chromosome 5. In contrast, the control BS181 p-subclones contained one or two copies of non-deleted rat chromosome 5. The conclusion is that a gene for the suppression of anchorage independence is located in the segment 5q22-23. We propose to call this gene SAI1 (for suppression of anchorage independence). Using Southern blotting, we tested whether any of several gene probes, known to correspond to DNA sequences in rat chromosome 5, were homologous to sequences in the deletion. Only one probe, corresponding to the active alpha1-interferon gene, was shown to be located within the deletion. Hence, the SAI1 gene is closely linked to the alpha 1-interferon gene, and might be identical to this locus.

Difluoromethylornithine, an effective new treatment of Gambian trypanosomiasis. Results in five patients.

Recent studies have shown DL-alpha-difluoromethylornithine (eflornithine), an inhibitor of polyamine biosynthesis, to be curative in various Trypanosoma species infections of laboratory animals. Five patients are described with Gambian trypanosomiasis treated in Belgium with difluoromethylornithine, using various intravenous and oral dosage schedules. Three patients had late-stage and two had early-stage disease. Difluoromethylornithine treatment was associated with clearing of parasites from blood within one to four days, a trend towards normalization of all altered biologic values associated with the disease, and marked amelioration of clinical symptoms. Side effects of difluoromethylornithine, including loose stools in three patients and both anemia, and a decrease in auditory acuity in one patient, were mild, transient, and never required interruption of drug treatment. The presence of difluoromethylornithine in cerebrospinal fluid, determined in three patients, demonstrated that difluoromethylornithine penetrates into the central nervous system. In three patients, follow-up of at least 24 months after treatment demonstrated a continued healthy state without evidence of relapse. These promising, albeit preliminary, results of difluoromethylornithine therapy, even in patients with central nervous system involvement, indicate that extended clinical trials are warranted to determine the optimal dosage regimen in patients with early- and late-stage disease.

Acquired immunodeficiency syndrome in African patients.

Between May 1979 and April 1983, 18 previously healthy African patients were hospitalized in Belgium with opportunistic infections (cryptococcosis, Pneumocystis carinii pneumonia, central-nervous-system toxoplasmosis, progressive cutaneous herpes simplex virus infection, disseminated cytomegalovirus infection, candidiasis, or cryptosporidiosis) or Kaposi's sarcoma, or with both. Ten of them died. During the same period five other patients were hospitalized with an illness consistent with a prodrome of the acquired immunodeficiency syndrome (chronic lymphadenopathy, fever, weight loss, and diarrhea). All patients tested had a marked decrease in helper T cells; an inversion of the normal ratio of helper to suppressor T cells, and a decreased or absent blastogenic response of lymphocytes to mitogens. Twenty patients had anergy. There was no evidence of an underlying immunosuppressive disease and no history of blood-product transfusion, homosexuality, or intravenous-drug abuse. This syndrome in patients originating in Central Africa is similar to the acquired immunodeficiency syndrome reported in American patients.