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U.S. National Institutes of Health
Cancer Diagnosis Program Cancer Imaging Program Cancer Therapy Evaluation Program Developmental Therapeutics Program Radiation Research Program Translational Research Program Biometric Research Branch Office of Cancer Complementary and Alternative Medicine

Aminoflavone Prodrug (NSC 710464)

Overview

The parent aminoflavone (NSC 686288) showed good differential activity in the NCI 60-cell line screen and marked effects in renal xenografts. This compound requires metabolic activation by CYP1A1 to exert its antiproliferative effects and the selectivity toward particular cell lines is related to the ability to induce CYP1A1 expression. In order to achieve a suitable formulation, a lysine derivative of the parent was prepared. PK studies show that the prodrug is rapidly converted to the parent in plasma.

Basic Chemistry

Preclinical Studies

  • in vitro
    • biochemical assays
    • 60 cell screen:
      • parent: Overall mean GI50 (5 experiments) is 6.9 µM. The most sensitive lines include CAKI-1 renal line (13 nM), MCF7 breast line (16 nM) and SW-630 colon line (32 nM). The least sensitive lines include M14 melanoma line (63 µM), SK-MEL-28 melanoma line (50 µM) and MOLT-4 leukemia line (50 µM).

        dose response | mean graph (GI50)

      • prodrug: Overall mean GI50 (2 experiments) is 3 µM. The most sensitive lines include MCF7 breast line (32 nM), IGROV1 ovarian line (40 nM) and NCI-H226 non-small cell lung line (40 nM). The least sensitive lines include SK-MEL-2 melanoma line (20 µM), HOP-92 non-small cell lung line (20 µM) and SNB-19 CNS line (20 µM).

        dose response | mean graph (GI50)

    • Yeast screen :
      • parent: no significant inhibition of yeast lines with specific mutations in cell cycle genes stage 0
    • other cell based assays
  • in vivo
    • formulations
    • efficacy studies
      • parent: confers highly significant activity against two of three renal carcinoma xenograft models, A-498 and CaKi-1 each exhibiting multiple tumor free animals. It was found to be inactive in several other xenograft models including SW-630 (colon), IGROV-I (ovarian), OVCAR-5 (ovarian) and RXF-393 (renal cell).
      • prodrug: active in both the CaKi-1 (renal ) and MCF-7(breast) xenograft models.
      • Screening data summary reports for individual experiments using the DTP invivo solid tumor and/or toxicity testing models are available below. Comments are based upon the results of individual experiments. Variations in outcome can result from changes in many experimental variables including the drug doses, administration routes, dosing schedules, drug vehicles, tumor models and tumor passage status.

        Parent: MCF7, CAKI-1, A498 Xenograft models

        Prodrug: Toxicity model; MCF7, CAKI-1 Xenograft models

  • Pharmaceutical Data
  • Toxicology
  • Pharmacology

Clinical Studies