B Kim-Triana | PubMed Health

PubMed1995

The hematon, a morphogenetic functional complex in mammalian bone marrow, involves erythroblastic islands and granulocytic cobblestones.

The development of pluripotential hematopoietic stem cells (PHSC) requires the continuous support provided by the bone tissue and bone marrow (BM) stromal cells. The basic rule of spatial and temporal organization of the distinct stromal cells and differentiating hematopoietic cells in the course of development, regenerative morphogenesis, or under homeostasis is still poorly understood. We have identified a cohort of preformed, multicellular aggregates in human BM aspirates that we have called hematons. This study shows that homologous hematon complexes can be isolated from the femoral BM shaft of normal mice. Cytologic analysis showed that both human and mouse hematons contained finely arborized endothelial cells, fibroblasts, preadipocytes, lipid-laden cells, and resident macrophages. This stromal cell web was tightly packed with hematopoietic cells comprising primitive cells with marrow-repopulating ability (MRA); day-8 and -12 colony-forming unit-spleen (CFU-S8 and -S12) in the mouse hematon; and high proliferative potential colony-forming cell (HPP-CFC), burst-forming unit-erythroid (BFU-E), granulocyte-macrophage-CFU (GM-CFU), as well as differentiated postmitotic cell populations in both human and mouse hematons. A cohort of single hematons produced a large, but variable, number of myeloid and erythroid cells, as well as megakaryocytes, in organotypic microculture, indicating the heterogenous growth potential of individual hematons. Each hematon developed into a complex, adherent colony in long-term liquid culture, which involves erythroblastic islands and granulocytic cobblestones. The hematons, isolated from 5-fluorouracil (5-FU)-treated mice, contained more HPP-CFC, BFU-E, and GM-CFU populations than the buffy coat (BC) fraction and produced significantly more CFU than normal hematons in organotypic microcultures. The present results provide further support for our hypothesis that the hematon is a tissue-specific complex structure that plays a critical roles in the maintenance of homeostasis and in the regenerative morphogenesis of mammalian BM.

Animals↗

PubMed1992

Phase I trial of Perrimustine, a new cysteamine (2-chloroethyl) nitrosourea: an intrapatient escalation scheme.

The recently synthesized nitrosourea, N-[N'-chloro-2-ethyl-N'-nitrosocarbamoyl]-S-methyl cysteamine sulfoxide (Perrimustine), is water soluble and has a high alkylating activity, similar to that of the widely used nitrsoureas BCNU and CCNU, and a low carbamoylating activity. Preclinical studies with a broad spectrum of murine tumors indicate that this new compound may be clinically useful. The maximally efficient dose range (MEDR) in L1210 bearing mice was 45 mg/m2 (subcurative dose) to 67 mg/m2 (subtoxic dose). The present phase I trial used an intrapatient escalation schedule, so that each patient entering the study received a potentially active dose. The first dose injected was 1:100 of the MEDR suboptimal dose to check for anaphylactic sensitivity. Patients were then given increasing doses at increasing time intervals until toxicity was observed. The highest dose was given on day 150-230. The main toxic effect was myelosuppression [five out of the 24 patients evaluated: one grade 4 thrombocytopenia, two grade 3 thrombocytopenia; anemia and leucopenia were milder (grade 1 to 2 on OMS scale)]. Of the 19 patients evaluated for clinical response, one showed response after the 45 mg/m2 dose (disappearance of the cerebral metastasis with persistence of hepatic localizations in a patient with melanoma) and the disease was stabilized in two cases (a pleural mesothelioma and a renal carcinoma with lung metastases) after 26 and 37 weeks, with total cumulative doses per m2 of 232 and 196 mg, respectively.

Adolescent↗