Synthesis and Antitumour activity of some aryl semicarbazones

Various 4-substituted phenyl semicarbazone derivatives were synthesized and evaluated in vitro by NCI in the 3-cell line, one dose primary anticancer assay. Three compounds showed significant activity against breast MCF7 cell line and were further evaluated for potential anticancer activity in an in vitro human disease-oriented tumour cell line screening panel that consisted of 60 human tumour cell lines arranged in nine subpanels, representing diverse histologies. Leukemia, colon, ovarian and breast cancer cell lines were relatively more sensitive to these compounds than the other cell lines. The 4-carboxy substituted p-nitrobenzylidene phenyl semicarbazone (1c) emerged as the most active compound with average GI50 value (the molar drug concentration required for the 50% growth inhibition) of 28.6µM. This compound showed greater activity than methotrexate against NCI-H226(Lung), BT-549 and T-47D(Breast) cancer cell lines

International collaboration in drug discovery and development. The United States National Cancer Institute experience

A research paper on international collaboration in drug discovery and development.In 1937, the United States National Cancer Institute (NCI) was established with its mission being "to provide for, foster and aid in coordinating research related to cancer". The NCI is the largest of seventeen Institutes which comprise the National Institutes of Health (NIH), which are components of the Federal Government's Department of Health and Human Services. The NCI and NIH are entirely funded through appropriations from the U.S. Congress and, as such, are entirely non-commercial and non-profit. Thus, while the NCI will attempt to license drugs discovered through its screening programs to pharmaceutical companies for advanced development and marketing, chemotherapeutic agents not licensed, but considered by NCI to be clinically effective, will be distributed by the NCI at no cost to the patients. An example is the antileukemic agent, Erwinia L-asparaginase, which was procured by the NCI and distributed free of charge until its production and marketing were transferred to the private sector. In 1955, NCI set up the Cancer Chemotherapy National Service Center (CCNSC) to promote a cancer chemotherapy program, involving the procurement, screening, preclinical development, and clinical evaluation of new agents. All aspects of drug discovery and preclinical development are now the responsibility of the Developmental Therapeutics Program (DTP), a major component of the Division of Cancer Treatment, Diagnosis and Centers (DCTDC). During the past 40 years, over 300,000 chemicals submitted by investigators and organizations worldwide, have been screened for antitumor activity, and NCI has played a major role in the discovery and development of almost all of the available commercial and investigational anticancer agents (Boyd 1993)

Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts

Molecular Cancer Therapeutics32111-121MCTO

Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27KIP1.

Altered and deregulated cyclin-dependent kinase (cdk) activity is now believed to play a major role in the pathogenesis of head and neck squamous cell carcinomas (HNSCC), thus providing a suitable cellular target for therapeutic intervention. UCN-01 (7-hydroxy-staurosporine), a known protein kinase C and cdk modulator, demonstrates antiproliferative and antitumor properties in many experimental tumor models and may represent a potential candidate to test in HNSCC. In this study, UCN-01 displayed potent antiproliferative properties (IC50 of ∼17–80 nm) in HNSCC cells. Cell cycle analysis revealed that UCN-01 treatment of HNSCC cells for 24 h leads to a G1 block with a concomitant loss of cells in S and G2-M and the emerging sub-G1 cell population, confirmed to be apoptotic by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. Additional in vitro studies demonstrated a G1 arrest that was preceded by depletion in cyclin D3, elevation of p21WAF1 and p27KIP1 leading to a loss in activity of G1 cdks (cdk2, cdk4), and reduction in pRb phosphorylation. Antitumor properties of UCN-01 were also assessed in vivo by treating HN12 xenografts (7.5 mg/kg/i.p./daily) with UCN-01 for 5 consecutive days. Total sustained abolition of tumor growth (P < 0.00001) was obtained with only one cycle of UCN-01 treatment. Terminal deoxynucleotidyl transferase-mediated nick end labeling staining of xenograft samples revealed a higher incidence of apoptosis in treated tissues when compared with control. Additional tissue analysis demonstrated that elevated p27KIP1 with minimal increase in p21WAF1 and reduced cyclin D3 levels were readily detected in those animals treated with UCN-01, similar to those observed in HNSCC cells. Thus, UCN-01 exhibits both in vitro and in vivo antitumor properties in HNSCC models, and these effects are associated with a decrease in cyclin D3 and an increase in p27KIP1 protein levels, thus providing appropriate surrogate markers to follow treatment efficacy in vivo and, therefore, a suitable drug candidate for treating HNSCC patients

The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein

The broad-range cyclin-dependent kinase inhibitor 7-hydroxystaurosporine (UCN-01) is known to induce both a G1 cell cycle arrest and apoptosis. The mechanism of UCN-01-induced apoptosis is largely unknown. We analysed the mechanism of cytotoxicity of UCN-01 in four established colon carcinoma cell lines. The cell lines SW48 and LS513 responded to UCN-01 treatment by undergoing apoptosis in a concentration-dependent manner while the cell lines HT-29 and WiDr were completely resistant. Apoptosis in LS513 and SW48 cell lines was concomitant with the suppression of Bcl-x(L) on mRNA and protein level. In contrast, in the apoptosis-resistant cell lines, Bcl-x(L) expression was not affected by UCN-01. Stable overexpression of the Bcl-x(L) protein abrogated UCN-01-triggered apoptosis, but only partially restored growth, indicating that both cell cycle arrest and apoptosis exert the anticancer effect in a coordinated manner. The inhibition of Akt phosphorylation did not correlate with the apoptotic phenotype. UCN-01 inhibited the activating STAT3 phosphorylations on Ser727 and, notably, on Tyr705, but STAT3 did not contribute to Bcl-x(L) expression in colon carcinoma cells. Moreover, we show for the first time that UCN-01 induces apoptosis by suppression of Bcl-x(L) expression. The inhibition of this pathway is a new aspect of cytotoxic and modulatory potential of UCN-01

Preclinical evaluation of amino acid prodrugs of novel antitumor 2-(4-amino-3-methylphenyl)benzothiazoles

Novel 2-(4-aminophenyl)benzothiazoles (e.g., compounds 1 and 2) possess highly selective, potent antitumor properties in vitro and in vivo. Elucidation of the mechanism of action of this structurally simple class of compounds has occurred in parallel with selection of a candidate clinical agent. Antitumor benzothiazoles induce and are biotransformed by cytochrome P 450 1A1 to putative active, as well as inactive metabolites. Metabolic inactivation of the molecule has been thwarted by isosteric replacement of hydrogen with fluorine atoms at positions around the benzothiazole nucleus. Amino acid conjugation to the exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles has been used to overcome limitations posed by drug lipophilicity. Water soluble, chemically stable prodrugs rapidly and quantitatively revert to their parent amine in mice, rats, and dogs in vivo. Plasma concentrations of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (2) regenerated from the lysylamide prodrug (2b), sufficient to elicit cytocidal activity against ZR-75–1 and T47D human mammary carcinoma cell lines persist >6 h. The growth of breast (MCF-7) and ovarian (IGROV-1) xenograft tumors is significantly retarded by 2b. Manageable toxic side effects are reported from preclinically efficacious doses of 2b. Cytochrome P 450 1A1 protein expression, selectively induced in sensitive carcinoma cells, was detected in MCF-7 and IGROV-1 tumors 24 h after treatment of mice with 2b (20 mg/kg). The lysyl amide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole is potentially suitable for clinical evaluation