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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What are topoisomerases?

• Topoisomerases are enzymes that either decrease
  the torsional stress of double stranded DNA (by
  reducing the number of times the strands are
  wrapped about each other) or increase the
  torsional stress (by increasing the number of
  times the strand are wrapped about each other).
• number of times the strands are wrapped about
  each other linking number
• There are various types of topoisomerases in both
  eukaryotes and prokaryotes. But camptothecin
  (CPT) specifically targets topoisomerase I (Topo
  I)

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Torsional Stress

• Strand unwinding at the replication fork during
  DNA replication, causes the parental DNA strands
  ahead of the fork to become over wound, causing
  torsional stress at the pre-fork region
• The net conservation of winding- deficiency in
  winding in one region of the DNA is compensated
  by over winding in another region of the
  structure

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Torsional Stress

• Torsional stress is the result of the DNA
  wrapping around chromosomal proteins. The DNA is
  topologically constrained.

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Torsional Stress

• The torsional stress at the pre-fork region must
  be relieved or the strand unwinding will be
  energetically unfavorable, and replication will
  terminate.

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Topo I Action

• Cleavage of a phosphodiester bond of the scissile
  strand and immobilization of the 5-end by a
  covalent bond formation between the DNA phosphate
  and a tyrosine residue (T-723).
• This results in the formation of a covalent
  intermediate complex, which CPT stabilizes

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Topo I Action

• Free Rotation of the 3-end around the
  non-cleaved strand, allowing for the relaxation
  of the strained structure

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Topo I Action

• Resealing of the strand by phosphodiester bond
  formation, followed by enzyme dissociation

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Active Site of Topo I
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The structure of Topo1
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CPT binding site
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DNA strand breakage

• Alteration of the stabilized complex Collision
  between the rep fork and the stabilized complex
  alters the complex, resulting in DNA breaks. How
  this process exactly occurs is unclear
• Alteration of DNA structure Arrest of the
  replication fork by the protein-DNA complex
  alters DNA Structure near the replication.
• For example, the presence of single-stranded DNA
  near the replication fork leads to the formation
  of Topo-I SS DNA complex, which have been known
  to undergo spontaneous DNA cleavage.
• Source Cancer Research 1989495077-82

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DNA replication is essential for cell damage

• CPTs are highly S-phase specific even though the
  level of camptothecin is constant between the G1,
  S, G2, and M phases of the cell cycle
• DNA synthesis inhibitors such as hydroxy-urea can
  protect cells from CPTinduced cytotoxicity.

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Areas for further research

• Actual mechanism of cell death following CPT
  administration has not yet been determined.
• Little is known about possible long-term
  toxicities of CPTs
• The overall contribution of SN-38 to irinotecan
  activity is yet unknown

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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.
  1998, 20(4) 161-172
• http//www.unc.edu/depts/chemistry/faculty/redinbo
  mr/mrrresproj.html