CI-921: an analog of amsacrine with experimental activity against solid tumors.

CI-921, a 4,5-disubstituted analog of amsacrine, has been selected for clinical testing because of its experimental activity in vitro and in vivo against solid tumors as well as leukemias. In studies conducted by Baguley and co-workers, CI-921 demonstrated activity against Lewis lung carcinoma in vivo, producing marked increases in life span and a high proportion of 60-day survivors. An intermittent schedule of administration was more effective than a daily X 5 or daily X 9 schedule. In pharmacokinetic studies in dogs, CI-921 achieved higher plasma concentrations and was cleared more slowly than amsacrine. CI-921 is readily soluble in water and may have antitumor activity when administered orally. Animal toxicology studies indicate that dose-related, reversible leukopenia and thrombocytopenia occur, as well as gastrointestinal toxicity, elevation of alkaline phosphatase and generalized lymphoid depletion. Phase I clinical testing of a parenteral formulation is in progress.

Similarities between stratum corneum basic protein and histidine-rich protein II from newborn rat epidermis.

The stratum corneum basic protein and histidine-rich protein II were each isolated from newborn rat epidermis and compared by biochemical and immunologic methods. The proteins were indistinguishable by immunodiffusion using antiserum elicited to either protein. The migration of the proteins on SDS-polyacrylamide gel electrophoresis was identical giving a molecular weight of 49 000. These proteins, which have similar but unusual amino acid compositions, give very similar tryptic peptide maps. Both proteins aggregate with keratin filaments to form macrofibrils. These results suggest that histidine-rich protein II and stratum corneum basic protein are the same protein. We suggest that this protein be called histidine-rich basic protein.

Molecular markers of differentiation in the epidermis of the newborn rat.

Regulation in epidermal differentiation can best be studied if molecular mechanism can be associated with structural and functional changes. Such recognized associations include the cessation of mitosis through inhibition of DNA replication by a G1-inhibitor present in the suprabasal cells, the biosynthesis of a tonofilament-protein as an early event in keratinization, the biosynthesis of HRP0 (histidine-rich protein) and its polymerization to HRPI during the formation of keratohyalin, the conversion of HRPI to HRPII coincident with the loss of the nucleus from the granular cell, and the aggregation of the stratum corneum basic protein and keratin filaments to form fibers in the cornified cell. To this list can now be added changes in specificity for lectin-binding to the cell surface as the keratinocyte progresses toward the cutaneous surface. This report presents data on a) the conversion of HRPI to HRPII and b) the differential lectin-binding in the epidermis of the newborn rat. HRPI (Mol. Wgt. greater than or equal to 10(6)) and HRPII (Mol. Wgt. 6 X 10(4)) have similar unique amino acid compositions and exhibit extensive-but not complete-homology in primary structures as determined by peptide mapping after exposure to trypsin. When labeled by exposure in vivo to radioactivity histidine, about 75 of the labeled histidine from both HRPI and HRPII appeared in one peptide fraction in the map, HRPI appears to have on histidine-containing fragment which is not present in HRPII. This peptide appears to contain phosphate and to account for the organically-bound phosphate which was found in HRPI but not defected in HRPII. Changes which occur in the lectin-binding specificity of the cell during differentiation may result from either movement or chemical change in carbohydrates at the cell surface. Immunofluorescent studies have shown that an isolectin from Bandieraea simplicifolia with specificity for alpha-D-galactose binds to the surface of basal and lower spinous cells, a lectin from Ulex europaeus with specificity for alpha-L-focus labels spinous cells, and a second lectin from B. simplicifolia with specificity for N-acetyl-D-glucosamine labels cornified cells. The relationship fo these alterations in the carbohydrates of the cell surface in intracellular structural and/or functional changes in unknown.