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Last Updated: 04/25/2012

Camptothecins (NSC 94600, 609699, 616348)

Overview

Camptothecin (NSC 94600) was first isolated by Wall 1 from a sample of Camptotheca acuminata2,3. Significant activity was seen in mouse models and the compound was developed for clinical studies. Initial phase I clinical trials in the 1970s (done with the carboxylate salt) showed evidence of antitumor activity in humans, but also severe and unpredictable toxicity. These results limited interest in this series of compounds until 1985, when it was shown that they work via a unique mechanism of action--inhibition of topoisomerase I4. Renewed interest led to further work on analogue synthesis, formulation, and pharmacology on compounds in this series5. In 1996, two camptothecin analogs were approved by the FDA, topotecan (NSC 609699) and irinotecan (NSC 616348).

Basic Chemistry

  • Chemical Names:
  • Chemical Structure: Camptothecins are pentacylic alkaloids with a lactone ring.
  • Solubility:
    • Camptothecin
      • DMSO — clear yellow solution at 1 mg/ml
      • Chloroform/methanol (4:1) — 4 mg/ml
    • Topotecan
      • Water — Soluble
      • Methanol — Soluble
      • Ethanol — Insoluble
      • Dimethylformamide — Soluble
    • Irinotecan
      • Water — Soluble

Preclinical Studies

  • in vitro
    • 60-cell line screen
      • Camptothecin — Overall mean GI50 is 4.4E-8 M. Most sensitive lines include MOLT-4 and SR leukemia lines (1E-8 M). Least sensitive lines include TK-10 renal line (1.3E-6 M) and the HS 578T breast line (7.9E- 7 M).
      • Topotecan — Overall mean GI50 is 1.6E-7 M. Most sensitive lines include MOLT-4 and CCRF-CEM leukemia lines (1.3E-8 M). Least sensitive lines include TK-10 renal line (6.3E-6 M) and the SNB-75 CNS line (5.0E-6 M).
      • Irinotecan — Overall mean GI50 is 1.4E-5 M. Most sensitive lines include MOLT-4 (1.6E-6 M) and SR leukemia lines (2.5E-7 M). Least sensitive lines include DLD-1 colon line (1.0E-4 M) and the SK-MEL-2 line (7.9E-5M).
    • Yeast Anticancer Screen
      • Camptothecin — Significant inhibition of yeast lines with specific mutations in cell cycle genes, especially rad52 and rad50.
      • Topotecan — Significant inhibition of yeast lines with specific mutations in cell cycle genes, especially rad52 and rad50.
      • Irinotecan  — No significant inhibition of yeast lines with specific mutations in cell cycle genes.
  • in vivo
    • Mouse Tumor Models:
      • Camptothecin — Significant activity in L1210 and P388 leukemia (ip Q4DX2, 15 mg/kg in saline with Tween-80). Some activity in B16 melanoma (ip Q1DX9, 3 mg/kg in saline with Tween-80), and Sarcoma M5076 (ip Q4DX4, 6 mg/kg in saline with Tween-80).
      • Topotecan — Significant activity in L1210 leukemia (ip Q4DX2, 40 mg/kg in saline with Tween-80).
      • Irinotecan — Significant activity in L1210 leukemia (ip Q4DX2, 89 mg/kg in water).
    • Human Xenograft Models:
      • Topotecan — Broadly active in a number of models including SF-295 CNS (ip Q4DX3, 13.5 mg/kg), U251- HRE CNS (ip Q1DX10, 25 mg/kg), HCT-116 colon (ip Q1DX5, 4 mg/kg), COLO205 colon (iv Q4DX2, 10 mg/kg), OVCAR-3 ovarian (ip Q1DX5, 2.5 mg/kg), and A498 renal (iv Q4DX2, 10 mg/kg).
      • Irinotecan — Active in a number of models including SF-295 CNS (iv, Q4DX2, 100 mg/kg), HT29 colon (iv Q4DX6, 60 mg/kg), OVCAR-3 ovarian (iv Q4DX2, 100 mk/kg), and A498 renal (iv Q4DX2, 100 mg/kg).

Clinical Studies

References

  1. Wall, ME, Wani, MC, Cook, CE, Palmer, KH, McPhail, HT, Sim, G.A. Plant antitumor agents I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc. 1996;88:3888-3890. http://pubs.acs.org/cgi-bin/archive.cgi/jacsat/1966/88/i16/pdf/ja00968a057.pdf

  2. Wall, ME; Camptothecin and Taxol: Discovery to Clinic. Med Res Rev. 1998;18:299-314.  http://www3.interscience.wiley.com/journal/80046/abstract

  3. http://dtp.nci.nih.gov/timeline/noflash/success_stories/s14_topotecan.htm

  4. Hsiang, YH, Hertzberg R, Hecht S, Liu LF; Camptothecin Induces Protein-linked DNA Breaks via Mammalian DNA topoisomerase I.  J Biol Chem. 1985;260:14873-8.  http://www.ncbi.nlm.nih.gov/pubmed/2997227

  5. Garcia-Carbonero R, Supko JG; Clin Can Res. 2002;8:641-61. http://www.ncdi.nlm.gov/pubmed/11895891,11025469,9358934