Disease relevance of CHS 828

• Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity [1].
• In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors [1].
• CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells [1].
• Temporal effects of the novel antitumour pyridyl cyanoguanidine (CHS 828) on human lymphoma cells [2].
• U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h [3].

High impact information on CHS 828

• The monitoring of p53 levels revealed that CHS 828 induced p53 response in a dose-dependent manner in only normal cells [4].
• Action of a novel anticancer agent, CHS 828, on mouse fibroblasts: increased sensitivity of cells lacking poly (ADP-Ribose) polymerase-1 [4].
• In a study using a panel of cell lines with different resistance patterns, the effects of CHS 828 showed a low correlation with the activity patterns of known anticancer agents, and no sensitivity to known mechanisms of multidrug resistance was observed [1].
• There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels [5].
• We have investigated the effect of CHS 828 on the nuclear factor-kappa B (NF-kappa B) because of its well-known role in the control of cell division and apoptosis [6].

Biological context of CHS 828

• Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity [6].
• The inhibition of the IKK activity by different CHS 828 analogues correlates well with the inhibition of NYH small cell lung cancer cell proliferation in vitro and in vivo [6].
• 1. The present study was aimed at elucidating the apoptosis inhibitory properties of the cyanoguanidine CHS 828 [7].
• The present results support the theory that CHS 828 block specific cell death pathways [7].
• In vitro analysis of tumour cell survival in response to CHS 828 revealed a cytotoxic effect progressively increased as a function of exposure time with maximum efficacy observed after 72 h [2].

Anatomical context of CHS 828

• The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested [3].
• In the present study, marked antitumoural activity of peroral CHS 828 was shown against three different human neuroendocrine tumours, midgut carcinoid (GOT1), pancreatic carcinoid (BON), and medullary thyroid carcinoma (GOT2), transplanted in nude mice [8].
• CHS 828 was significantly more active against hematological malignancies compared to normal lymphocytes [9].

Associations of CHS 828 with other chemical compounds

• Modulation of pyridyl cyanoguanidine (CHS 828) induced cytotoxicity by 3-aminobenzamide in U-937 GTB cells [10].
• Combination therapy induced tumor regression at d 4 with CHS plus TNP and d 6 with CHS plus SU5416, compared with d 14 with CHS 828 alone (p < 0.05), and complete tumor regression was seen in nine of 19 animals (47%) [11].
• The pharmacokinetics of CP and CHS 828 were both described by one-compartment models [12].

Gene context of CHS 828

• We investigated the effect of CHS 828 on p53 response in normal and tumor cells and compared this effect with that exerted by conventional anticancer drugs [13].
• Moreover, CHS 828 has also been shown to inhibit the LPS-induced degradation of the I kappa B alpha and I kappa B beta in THP-1 cells, leading us to identify the I kappa B kinase complex as a molecular target of CHS 828 [6].
• CHS 828 has low toxicity and lacks known patterns of multidrug resistance [11].
• CHS 828 inhibits neuroblastoma growth in mice alone and in combination with antiangiogenic drugs [11].
• Antitumoural Effects of the Pyridyl Cyanoguanidine CHS 828 on Three Different Types of Neuroendocrine Tumours Xenografted to Nude Mice [8].

Analytical, diagnostic and therapeutic context of CHS 828

• CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer [1].
• In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped [1].
• CHS 828 is now in early clinical trials, the results of which are eagerly awaited [14].
• Combination treatment of CHS 828 and TNP-470 decreased the total viable tumor volume by 71% compared with treatment with CHS 828 alone [11].
• Between 44 and 72 h of CHS 828 exposure, there was an increasing frequency of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) positive cells indicative of apoptosis, but caspase-3 was only modestly increased and caspases-8 and -9 showed no activation upon CHS 828 exposure [15].

References