Epidermal growth factor receptor-dependent cytotoxic effect by an EGF-ribonuclease conjugate on human cancer cell lines: A trial for less immunogenic chimeric toxin

Hiromitsu Jinno, Masakazu Ueda, Soji Ozawa, Kiyoshi Kikuchi, Tadashi Ikeda, Koji Enomoto, Masaki Kitajima

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Mammalian pancreatic ribonuclease (RNase) was conjugated chemically via a disulfide bond to human or murine epidermal growth factor (EGF). The conjugation between EGF and RNase was ascertained by SDS-PAGE using reduced and nonreduced conjugates. The EGF-RNase conjugate retained potent RNase activity and competed with 125I-EGF for binding to EGFR to the same extent as unconjugated EGF. Both the human and murine EGF-RNase conjugates showed dose-dependent cytotoxicity against EGFR-overexpressing A431 human squamous carcinoma cells with IC50 values of 3 x 10-7 M and 6 x 10-7 M, respectively, whereas free RNase had an IC50 of 10-4 M. Against the EGFR-deficient small-cell lung cancer cell line H69, the EGF-RNase conjugate had no cytotoxic effect. The Human EGF-RNase conjugate showed dose-dependent cytotoxicity against other squamous carcinoma cell lines (TE-5, TE-1) and breast cancer cell lines (BT-20, SK-BR-3, MCF-7) and the cytotoxicity of the conjugate correlated positively with the level of expression of EGFR by each cell line. An unconjugated mixture of EGF and RNase had no greater effect than RNase alone on any cell line. Excess free EGF blocked EGF-RNase conjugate cytotoxicity against A431 cells. These results suggest that the EGF-RNase conjugate may be a more effective anticancer agent with less immunogenicity than conventional chimeric toxins.

Original languageEnglish
Pages (from-to)303-308
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume38
Issue number4
DOIs
Publication statusPublished - 1996 Jul 19

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Keywords

  • Breast cancer
  • Conjugate
  • EGF
  • Esophageal cancer
  • Ribonuclease

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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