Camptothecin

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Camptothecin

• Conni Covington
• Seboo Dhakhwa

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What is Camptothecin?

• Camptothecin is an alkaloid produced by
  Camptotheca acuminata and Mappia foetida
• Irinotecan is a less toxic, more water-soluble
  derivative of camptothecin
• Irinotecan is sold under the name Camptosar by
  Pharmacia Upjohn.

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Indications

• First-line treatment of metastatic cancers of the
  colon and rectum
• Treatment of cancers of the colon and rectum that
  have progressed following treatment with 5FU/LV

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Unlabeled Uses

• Cancers of the lung, cervix, pancreas, breast,
  and stomach leukemia, lymphoma

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Contraindications and Precautions

• Contraindications
• Pregnancy (category D)
• Breastfeeding
• Neutropenic fever (discontinue)

• Precautions
• Hepatic dysfunction (adjust dose)
• Hyperbilirubinemia

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Metabolism

• Primary route by P450s inactive metabolite
• Minor route by carboxyesterases active
  metabolite SN-38
• Minor route inhibition can lead to buildup of
  toxic SN-38

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Adverse Reactions

• Alopecia
• Diarrhea
• Vomiting
• Weakness
• Neutropenia
• Fever
• Stomach pain and cramping
• Dyspnea

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Dosage schedule

• May be every week or every three weeks, according
  to administered dose
• Varies according to single treatment or
  combination treatment
• May require adjustment based on severity of side
  effects

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Topoisomerase I

• Binds to DNA molecule beyond the replication fork
• Cleaves a phosphodiester bond on one strand of
  DNA and binds to the cleaved site
• Reduces torsional strain on the molecule during
  replication
• May be involved in RNA transcription

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Inhibition of Topo I by camptothecin

• Camptothecin stabilizes the cleavable complex so
  that the nick in the DNA is not religated
• When the replication fork reaches the
  camptothecin-bound complex, it results in a
  replication-halting double-strand break
• Specific to S-phase of the cell cycle

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References

• Lexi-Comp online
• Clinical Pharmacology Online
• Liu, Leroy F. Annu. Rev. Biochem, 1989. 58
  351-375
• Herben, Virginie M.M. et al. Pharm. World Sci.
  199820(4) 161-172