Preclinical pharmacology of the pyrrolobenzodiazepine (PBD) monomer DRH-417 (NSC 709119).
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 IC(50) = 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 signaling pathway.
Burger
A M
AM
Department of Pharmacology & Experimental Therapeutics, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA. aburger@som.umaryland.edu
Loadman
P M
PM
Thurston
D E
DE
Schultz
R
R
Fiebig
H H
HH
Bibby
M C
MC
D000818:Animals; D000876:Anthramycin / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001569:Benzodiazepines / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D020869:Gene Expression Profiling; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D011758:Pyrroles / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; C518692:DRH-417; D011758:Pyrroles; D000876:Anthramycin; D001569:Benzodiazepines