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Camptothecin

Camptothecin. Conni Covington Seboo Dhakhwa. 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

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Camptothecin

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  1. Camptothecin Conni Covington Seboo Dhakhwa

  2. 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.

  3. 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

  4. Unlabeled Uses • Cancers of the lung, cervix, pancreas, breast, and stomach; leukemia, lymphoma

  5. Contraindications: Pregnancy (category D) Breastfeeding Neutropenic fever (discontinue) Precautions: Hepatic dysfunction (adjust dose) Hyperbilirubinemia Contraindications and Precautions

  6. 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

  7. Adverse Reactions • Alopecia • Diarrhea • Vomiting • Weakness • Neutropenia • Fever • Stomach pain and cramping • Dyspnea

  8. 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

  9. 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 wrappedabout 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)

  10. 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

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

  12. 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.

  13. 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

  14. Topo I Action • Free Rotation of the 3’-end around the non-cleaved strand, allowing for the relaxation of the strained structure

  15. Topo I Action • Resealing of the strand by phosphodiester bond formation, followed by enzyme dissociation

  16. Active Site of Topo I

  17. The structure of Topo1

  18. CPT binding site

  19. 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 1989;49;5077-82

  20. 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 CPT–induced cytotoxicity.

  21. 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

  22. 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/redinbomr/mrrresproj.html

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