Preclinical pharmacology of novel indolecarboxamide ML-970, an investigative anticancer agent
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 GI50 of 34 nM. The aim of this study is to define the pharmacological properties of this novel anticancer agent.
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.
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.
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.
KeywordsML-970 (NSC 716970) Indolecarboxamide HPLC Protein binding Pharmacokinetics Enterohepatic circulation
This work was supported by NIH NCI contract N01-CM-52207. We thank Dr. Silvana Grau, Dr. Scharri Ezell, and Ms. Charnell Sommers for excellent technical assistance, and Dr. Donald Hill for helpful discussion.
- 1.Sato A, McNulty L, Cox K, Kim S, Scott A, Daniell K, Summerville K, Price C, Hudson S, Kiakos K, Hartley JA, Asao T, Lee M (2005) A novel class of in vivo active anticancer agents: achiral seco-amino- and seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) analogues of the duocarmycins and CC-1065. J Med Chem 48:3903–3918PubMedCrossRefGoogle Scholar
- 4.Kiakos K, Sato A, Asao T, McHugh PJ, Lee M, Hartley JA (2007) DNA sequence selective adenine alkylation, mechanism of adduct repair, and in vivo antitumor activity of the novel achiral seco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145. Mol Cancer Ther 6:2708–2718PubMedCrossRefGoogle Scholar
- 8.Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L (2010) Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res 16:1726–1736PubMedCrossRefGoogle Scholar
- 10.Bernillon P, Bois FY (2000) Statistical issues in toxicokinetic modeling: a bayesian perspective. Environ Health Perspect 108(Suppl 5):883-893Google Scholar