Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 6, pp 1423–1431 | Cite as

Preclinical pharmacology of novel indolecarboxamide ML-970, an investigative anticancer agent

  • Elizabeth Rayburn
  • Wei Wang
  • Mao Li
  • Xu Zhang
  • Hongxia Xu
  • Haibo Li
  • Jiang-Jiang Qin
  • Lee Jia
  • Joseph Covey
  • Moses Lee
  • Ruiwen Zhang
Original Article

Abstract

Purpose

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.

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.

Keywords

ML-970 (NSC 716970) Indolecarboxamide HPLC Protein binding Pharmacokinetics Enterohepatic circulation 

Notes

Acknowledgments

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.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Elizabeth Rayburn
    • 1
  • Wei Wang
    • 1
    • 2
    • 3
  • Mao Li
    • 1
  • Xu Zhang
    • 1
    • 2
  • Hongxia Xu
    • 1
    • 2
  • Haibo Li
    • 1
  • Jiang-Jiang Qin
    • 2
  • Lee Jia
    • 4
  • Joseph Covey
    • 4
  • Moses Lee
    • 5
  • Ruiwen Zhang
    • 1
    • 2
    • 3
  1. 1.Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, Cancer Pharmacology Laboratory, Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Pharmaceutical SciencesTexas Tech University Health Sciences CenterAmarilloUSA
  3. 3.Cancer Biology Center, School of PharmacyTexas Tech University Health Sciences CenterAmarilloUSA
  4. 4.Developmental Therapeutics Program, DCTDNCIRockvilleUSA
  5. 5.Department of ChemistryHope CollegeHollandUSA

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