title: Preclinical pharmacology of novel indolecarboxamide ML-970, an investigative anticancer agent.
abstract: OBJECTIVE
  ML-970 (AS-I-145; NSC 716970) is an indolecarboxamide synthesized as a less toxic analog of CC-1065 and duocarmycin, a natural product that binds the A-T-rich DNA minor groove and alkylates DNA. The NCI60 screening showed that ML-970 had potent cytotoxic activity, with an average GI(50) of 34 nM. The aim of this study is to define the pharmacological properties of this novel anticancer agent.
  
  
  METHODS
  We established an HPLC method for the compound, examined its stability, protein binding, and metabolism by S9 enzymes, and conducted pharmacokinetic studies of the compound in two strains of mice using two different formulations.
  
  
  RESULTS
  ML-970 was relatively stable in plasma, being largely intact after an 8-h incubation in mouse plasma at 37°C. The compound was extensively bound to plasma proteins. ML-970 was only minimally metabolized by the enzymes present in S9 preparation and was not appreciably excreted in the urine or feces. The solution formulation provided higher C(max), AUC, F values, and greater bioavailability, although the suspension formulation resulted in a later T(max) and a slightly longer T(1/2). To determine the fate of the compound, we accomplished in-depth studies of tissue distribution; the results indicated that the compound undergoes extensive enterohepatic circulation.
  
  
  CONCLUSIONS
  The results obtained from this study will be relevant to the further development of the compound and may explain the lower myelotoxicity of this analog compared to CC-1065.
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, Cancer Pharmacology Laboratory, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rayburn
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Mao
authors.initials: M
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Xu
authors.forename: Haibo
authors.initials: H
authors.lastname: Li
authors.forename: Jiang-Jiang
authors.initials: JJ
authors.lastname: Qin
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Joseph
authors.initials: J
authors.lastname: Covey
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D015507:Drugs, Investigational / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D015507:Drugs, Investigational; D007211:Indoles; C574036:N-(4-amino-1-(2-chloroethyl)naphthalen-2-yl)-5,6,7-trimethoxy-1H-indole-2-carboxamide; D015057:1-Naphthylamine