Correlation between Plant Growth Regulator Release Rate and Bioactivity for the Series of Newly Synthesized Phytoactive Polymers

Phytoactive polymers are high molecular weight systems in which a plant growth regulator (PGR) unit is attached to the polymeric chain by a hydrolyzable chemical bond. The release rate of the PGR is linked to the biological activity of the phytoactive polymer and can be controlled by properties inherent in the whole macromolecular system. In this study the correlation of biological activity and plant growth regulator hydrolytic release rate was investigated for the series of newly synthesized 2,4-dichlorophenoxyacetic acid (2,4-D) polymeric esters. The polymers synthesized differ in their molecular weight, side group structure, and 2,4-D residue content. The influence of these polymer characteristics on the 2,4-D hydrolytic release was investigated, and it was demonstrated that hydrolysis rate substantially depends on the polymer molecular weight, side group structure, and 2,4-D residue content. It was also demonstrated that phytoactive polymer bioactivity depends on the hydrolysis rate of the polymers, and in dependence of this parameter can provide stimulating or inhibiting activity. Biological activity was illustrated by the elongation of wheat and barley coleoptiles.     

A New Mathematical Model for the Interpretation of Translational Research Evaluating Six CTLA-4 Polymorphisms in High-Risk Melanoma Patients Receiving Adjuvant Interferon

Adjuvant therapy of stage IIB/III melanoma with interferon reduces relapse and mortality by up to 33% but is accompanied by toxicity-related complications. Polymorphisms of the CTLA-4 gene associated with autoimmune diseases could help in identifying interferon treatment benefits. We previously genotyped 286 melanoma patients and 288 healthy (unrelated) individuals for six CTLA-4 polymorphisms (SNP). Previous analyses found no significant differences between the distributions of CTLA-4 polymorphisms in the melanoma population vs. controls, no significant difference in relapse free and overall survivals among patients and no correlation between autoimmunity and specific alleles. We report new analysis of these CTLA-4 genetic profiles, using Network Phenotyping Strategy (NPS). It is graph-theory based method, analyzing the SNP patterns. Application of NPS on CTLA-4 polymorphism captures allele relationship pattern for every patient into 6-partite mathematical graph P. Graphs P are combined into weighted 6-partite graph S, which subsequently decomposed into reference relationship profiles (RRP). Finally, every individual CTLA-4 genotype pattern is characterized by the graph distances of P from eight identified RRP''s. RRP''s are subgraphs of S, collecting equally frequent binary allele co-occurrences in all studied loci. If S topology represents the genetic “dominant model”, the RRP''s and their characteristic frequencies are identical to expectation-maximization derived haplotypes and maximal likelihood estimates of their frequencies. The graph-representation allows showing that patient CTLA-4 haplotypes are uniquely different from the controls by absence of specific SNP combinations. New function-related insight is derived when the 6-partite graph reflects allelic state of CTLA-4. We found that we can use differences between individual P and specific RRPs to identify patient subpopulations with clearly different polymorphic patterns relatively to controls as well as to identify patients with significantly different survival.     

Sclareol induces apoptosis in human HCT116 colon cancer cells <Emphasis Type="Italic">in vitro</Emphasis> and suppression of HCT116 tumor growth in immunodeficient mice

Labd-14-ene-8, 13-diol (sclareol) is a labdane-type diterpene, which has demonstrated significant cytotoxic activity against human leukemic cell lines, but its effect on solid tumor-derived cells is uknown. Here, we demonstrate that addition of sclareol to cultures of human colon cancer HCT116 cells results in inhibition of DNA synthesis, arrest of cells at the G₁ phase of the cell cycle, activation of caspases-8, -9, PARP degradation, and DNA fragmentation, events characteristic of induction of apoptosis. Intraperitoneal (ip) administration of sclareol alone, at the maximum tolerated dose, was unable to induce suppression of growth of HCT116 tumors established as xenografts in immunodeficient SCID mice. In contrast, ip administration of liposome-encapsulated sclareol, following a specific schedule, induced suppression of tumor growth by arresting tumor cell proliferation as assessed by detecting the presence of the cell proliferation-associated nuclear protein, Ki67, in thin tumor sections. These findings suggest that sclareol incorporated into liposomes may possess chemotherapeutic potential for the treatment of colorectal and other types of human cancer.