Aberrant DNA Damage Response and DNA Repair Pathway in High Glucose Conditions  - Pages 64-74

Amy Zhong, Melissa Chang, Theresa Yu, Raymond Gau, Daniel J. Riley, Yumay Chen and Phang-Lang Chen

DOI: http://dx.doi.org/10.6000/1929-2279.2018.07.03.1

Published: 25 June2018

Abstract: Background: Higher cancer rates and more aggressive behavior of certain cancers have been reported in populations with diabetes mellitus. This association has been attributed in part to the excessive reactive oxygen species generated in diabetic conditions and to the resulting oxidative DNA damage. It is not known, however, whether oxidative stress is the only contributing factor to genomic instability in patients with diabetes or whether high glucose directly also affects DNA damage and repair pathways.

Results: Normal renal epithelial cells and renal cell carcinoma cells are more chemo- and radiation resistant when cultured in high concentrations of glucose. In high glucose conditions, the CHK1-mediated DNA damage response is not activated properly. Cells in high glucose also have slower DNA repair rates and accumulate more mutations than cells grown in normal glucose concentrations. Ultimately, these cells develop a transforming phenotype.

Conclusions: In high glucose conditions, defective DNA damage responses most likely contribute to the higher mutation rate in renal epithelial cells, in addition to oxidative DNA damage. The DNA damage and repair are normal enzyme dependent mechanisms requiring euglycemic environments. Aberrant DNA damage response and repair in cells grown in high glucose conditions underscore the importance of maintaining good glycemic control in patients with diabetes mellitus and cancer. 

Keywords: Diabetes, DNA damage response, ATR, checkpoint kinase 1, Chemo resistant.

Early Phase I Results for 4-Demethyl-4-cholesteryloxypenclo-medine [DM-CHOC-PEN] as Therapy in Adolescent and Young Adult (AYA) Subjects with Advanced Malignancies  - Pages 75-78

L.R. Morgan, R.S. Weiner, M.L. Ware, M. Bhandari, T. Mahmood and P. Friedlander

DOI: http://dx.doi.org/10.6000/1929-2279.2018.07.03.2

Published: 25 June2018

Abstract: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine carbonate with a MOA via bis-alkylation of DNA @ N⁷-guanine and N⁴-cytosine that has completed adult clinical Phase I and II trials in individuals with malignancies involving the CNS. We report here objective clinical observations seen in a clinical Phase I DM-CHOC-PEN trial with AYA subjects that have cancer (some of which had CNS involvement).

Subjects & Methods: DM-CHOC-PEN was administered as a single 3-hr IV infusion once every 21 days in escalating doses from 50 – 98.7 mg/m² to individuals (aged 15-39 years of age) with advanced malignancies.

Results: Twelve (12) AYA individuals have been treated to date (with or without CNS involvement). The drug was well tolerated with fatigue (17%) being the most common adverse effect. No neuro/cognitive, liver dysfunction, hematological, cardiac, renal or GI toxicities were observed. Pharmacokinetic profiling revealed higher AUCs for all dose levels (50-98.7 mg/m²) than had been seen previously in adults. Three (3) AYA individuals treated (1 each with NSCLC, ALL, and astrocytoma involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier) and OS from 8 to 35+ mos.

Conclusion: DM-CHOC-PEN is safe in doses of 50-98.7 mg/m² and produced objective responses with improved OS and manageable toxicities in AYA individuals with malignancies involving the CNS. Complete data on subject responses and observed toxicities will be presented. The data support a 3-stage mechanism for tumor cytotoxicity: entry into the CNS and into the tumor via reversible binding to RBC membranes; then transported into cancer cells with L-glutamine; and bis-alkylation as described above.

Keywords: Cancer, central nervous system, metastatic, primary, DM-CHOC-PEN, non-neurotoxicity.