Preclinical pharmacology of the pyrrolobenzodiazepine (PBD) monomer DRH-417 (NSC 709119)

Burger, A.M., Loadman, P.M., Thurston, D.E., Schultz, R., Fiebig, H.H. and Bibby, M.C. (2007) Preclinical pharmacology of the pyrrolobenzodiazepine (PBD) monomer DRH-417 (NSC 709119). Journal of Chemotherapy, 19 (1). pp. 66-78.

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The pyrrolobenzodiazepine monomer DRH-417 is a member of the anthramycin group of anti-tumor antibiotics that bind covalently to the N2 of guanine within the minor groove of DNA. DRH-417 emerged from the EORTC-Drug Discovery Committee and NCI 60 cell line in vitro screening programs as a potent antiproliferative agent with differential sensitivity towards certain cancer types such as melanoma, breast and renal cell carcinoma (mean IC50 = 3 nM). DRH-417 was therefore tested for in vivo activity. The maximum tolerated dose (MTD) was established as 0.5 mg/kg given i.p. Marked anti-tumor activity was seen in two human renal cell cancers, one breast cancer and a murine colon tumor model (p<0.01). A selective HPLC (LC/MS) analytical method was developed and plasma pharmacokinetics determined. At a dose of 0.5 mg kg -1, the plasma AUC was 540 nM h (197.1 ng h ml-1) and the peak plasma concentration (171 nM [62.4 ng ml-1]) occurred at 30 min., reaching doses levels well above those needed for in vitro antiproliferative activity. Genomic profiling of in vivo sensitive tumors revealed that the latter have an activated insulin-like growth factor signalling pathway.

Item Type:Article
Uncontrolled Keywords:Anti-tumor activity; Minor groove DNA binder; PBD monomer; Plasma pharmacokinetics
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:2901
Journal or Publication Title:Journal of Chemotherapy
Deposited By:Library Staff
Deposited On:02 Mar 2012 16:55
Last Modified:02 Mar 2012 16:55

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