Synthesis and biological evaluation of EC140: a novel folate-targeted vinca alkaloid conjugate

Bioconjug Chem. 2006 Sep-Oct;17(5):1226-32. doi: 10.1021/bc060145g.

Abstract

A novel folate conjugate of desacetylvinblastine monohydrazide (DAVLBH), herein referred to as EC140, was designed and evaluated for biological activity against folate receptor (FR)-positive cells and tumors. EC140 was produced by coupling a peptidic analogue of the vitamin folic acid to DAVLBH via an acylhydrazone bond. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Initial in vivo tests confirmed EC140's activity in both syngeneic and xenograft models. Hence, enduring complete responses were observed in animals bearing established, subcutaneous tumors prior to therapy using regimens that produced minor toxicity. In contrast, treatment with the unconjugated DAVLBH drug produced nominal efficacy when dosed at its MTD. Overall, EC140's performance in vitro and in vivo warrants further preclinical study before this novel targeted chemotherapeutic is considered for clinical investigation.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / therapeutic use
  • Carrier Proteins / metabolism
  • Cell Line
  • Dose-Response Relationship, Drug
  • Folate Receptors, GPI-Anchored
  • Folic Acid / chemistry*
  • Folic Acid / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Neoplasm Transplantation
  • Neoplasms / drug therapy
  • Pterins / chemical synthesis*
  • Pterins / chemistry
  • Pterins / metabolism*
  • Pterins / therapeutic use
  • Receptors, Cell Surface / metabolism
  • Transplantation, Heterologous
  • Vinca Alkaloids / chemical synthesis*
  • Vinca Alkaloids / chemistry
  • Vinca Alkaloids / metabolism*
  • Vinca Alkaloids / therapeutic use

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • EC140 compound
  • Folate Receptors, GPI-Anchored
  • Pterins
  • Receptors, Cell Surface
  • Vinca Alkaloids
  • Folic Acid