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The study of substances that inhibit cell proliferation is hampered by the fact that a great many substances will inhibit proliferation in a non-specific way, simply by virtue of their toxic effects. A new assay has been developed, however, to study the proliferation of primitive stem cells in bone marrow in tissue culture dishes. Stem cells are primitive cells that can reproduce and give rise to a variety of different descendent cells. Using this assay, a substance initially called SCI, or stem cell inhibitor, was identified. As the biochemical analysis of SCI continued, it became clear that SCI was identical with the macrophage inflammatory protein-1 alpha, or MIP-1 alpha. This substance is a highly specific inhibitor of stem cell proliferation, and has no effect on the replication of blood progenitor cells, which have already become committed to their adult role. Electrophoresis revealed that the molecule is about 8,000 daltons in molecular weight, but the active substance in tissue culture may exist in complexes that have higher molecular weight. Molecular cloning of the gene for MIP-1 alpha also resulted in the unexpected finding of a closely related substance, known as MIP-1 beta. This substance has no apparent effect on the stem cell colony-forming assay that was used to identify MIP-1 alpha. These findings demonstrate not only that the effect observed with MIP-1 alpha is highly specific, but also that these molecules may be a part of a larger family of molecules, which play a role in the regulation of hematopoiesis, or blood cell production. The inhibition of proliferating stem cells by MIP-1 alpha may have direct clinical importance. Since chemotherapeutic agents kill proliferating cells, whether they are normal or cancerous, the hematopoietic cells are often the first to take a beating during the treatment of cancer patients. Indeed, the toxicity of chemotherapeutic agents for these cells is one of the factors which limits the dosage of chemotherapy. If MIP-1 alpha could be used to temporarily inhibit stem cell proliferation, these cells would be removed from the list of potential targets for chemotherapy; not only would a serious side effect be reduced, but higher and possibly more effective doses of chemotherapy might then be administered. (Consumer Summary produced by Reliance Medical Information, Inc.)

When investigating the biological effects of ionizing radiation on the haemopoietic system, a confounding problem lies in possible differences between the biological effects of sparsely ionizing, low linear energy transfer radiation such as X-, beta- or gamma-rays, and densely ionizing, high linear energy transfer radiation such as alpha-particles. To address this problem we have developed novel techniques for studying haemopoietic cells irradiated with environmentally relevant doses of alpha-particles from a plutonium-238 source. Using a clonogenic culture system, cytogenetic aberrations in individual colonies of haemopoietic cells derived from irradiated stem cells have been studied. Exposure to alpha-particles (but not X-rays) produced a high frequency of non-clonal aberrations in the clonal descendants, compatible with alpha-emitters inducing lesions in stem cells that result in the transmission of chromosomal instability to their progeny. Such unexpected instability may have important implications for radiation leukaemogenesis.