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[Protein synthesis inhibitor--antitumor activity and mode of action of KRN 5500]

H Kawai1

  • 1Pharmaceutical Division, Kirin Brewery Co., Ltd.

Gan to Kagaku Ryoho. Cancer & Chemotherapy
|October 6, 1997
PubMed

Insights

KRN 5500, an antitumor compound, effectively inhibited colon cancer liver metastasis in mice. Its active metabolite, SAN-Gly, determines KRN 5500

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • KRN 5500 is a novel semi-synthetic antitumor agent derived from spicamycin.
  • It exhibits broad-spectrum antitumor activity against various human cancer xenografts in mice.

Purpose of the Study:

  • To evaluate the therapeutic efficacy of KRN 5500 against liver metastasis of human colon cancer.
  • To identify the active metabolite of KRN 5500 and elucidate its mechanism of action.

Main Methods:

  • Treatment of severe combined immunodeficient (SCID) mice with liver metastasis using KRN 5500.
  • Measurement of tumor growth inhibition and serum TPA concentration.
  • In vitro protein synthesis inhibition assays using rabbit reticulocyte lysates.
  • Metabolite analysis using thin-layer chromatography (TLC) in human cancer and normal cell lines.

Main Results:

  • KRN 5500 treatment significantly inhibited liver tumor growth and normalized serum TPA levels.
  • KRN 5500 inhibits protein synthesis; SAN-Gly was identified as the potent active metabolite.
  • A strong correlation was observed between KRN 5500 cytotoxicity and its conversion to SAN-Gly in cancer cells.

Conclusions:

  • SAN-Gly is the intracellular active metabolite responsible for KRN 5500's antitumor effects.
  • The conversion activity from KRN 5500 to SAN-Gly is a key determinant of its cytotoxicity.
  • KRN 5500 demonstrates therapeutic potential for liver metastasis, with SAN-Gly as the critical effector.

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