Balanehru Subramanian

Inhibition of macromolecular synthesis by cryptophycin-52.

Cryptophycin (CP)-52, a synthetic analog of CP-1, possesses potent and selective antiproliferative activity against human solid tumors both in vitro and in vivo. Based on an algorithm developed in this laboratory using HCT-116 human colon adenocarcinoma cells, CP-52 exhibited a time- and concentration-dependent antiproliferative effect in the in vitro clonogenic assay. Inhibition of both DNA and RNA synthesis was observed in the absence of any effect on protein synthesis following a 24-h exposure to CP-52, at a time when proliferating cells were arrested in the G2/M phase of the cell cycle. In summary, we interpret these data to indicate that the selective inhibition of DNA synthesis may be a major causative factor responsible for the antiproliferative activity of CP-52 and subsequent G2/M arrest.

From FISH to Proteomics

Technological milestones in genomics have initiated a new approach in the development of novel anticancer drugs to specific genes. However, the heterogeneity of cancer involving multigene complexity calls upon a complementary approach to effectively develop novel anticancer drugs either to specific tumors or with broad range of anti-tumor activity. Among various techniques, fluorescence in situ hybridization (FISH) provides the opportunity to identify mRNA sequences at the subcellular level and has, therefore, become an important tool in gene expression studies. In our drug discovery and development program, we adopt a new hypothesis focusing on the whole cancer cell as a single target. A component of our unique developmental paradigm includes a drug-action profile paradigm defining the drug-specific antiproliferative effects of newly discovered investigational agents, at the molecular level using a genomic-proteomic interface. Such an approach using multicolor fluorescence hybridization on cDNA microarray and two-dimensional gel electrophoresis called, Painting with a Molecular Brush, has been successfully adopted to unravel the mechanism of action of a new anticancer agent, XK469.