# Camptothecin
**Camptothecin** (CPT) is a naturally occurring, pentacyclic quinoline alkaloid isolated from the bark of the Chinese tree *Camptotheca acuminata* (喜树, the "happy tree") that selectively inhibits the nuclear enzyme DNA topoisomerase I and serves as the parent compound of the anticancer drugs irinotecan and topotecan.[1](https://www.sciencedirect.com/science/article/pii/S0960894X16313646) • [2](https://www.ncbi.nlm.nih.gov/mesh/68002166) It was first discovered and isolated by Monroe E. Wall and Mansukh C. Wani in 1966 during a screening of plant species, and the extract showed substantial antitumor activity in vitro and in a mouse leukemia model, consistent with the tree's use in Traditional Chinese Medicine as a remedy against cancer.[1](https://www.sciencedirect.com/science/article/pii/S0960894X16313646) • [3](https://jamanetwork.com/journals/jama/article-abstract/661161)
| Key fact | Detail |
|---|---|
| Source and discovery | Isolated in 1966 by Wall and Wani from the bark of *Camptotheca acuminata*; structure determined by x-ray diffraction the same year[1](https://www.sciencedirect.com/science/article/pii/S0960894X16313646) • [4](https://discover.nci.nih.gov/kohn/book/drugs_against_cancer_chapter11_v220928br3.pdf) |
| Molecular target | Human DNA topoisomerase I, the only known target of the alkaloid; CPT blocks the religation step of the cleavage/religation reaction, stabilizing the covalent "cleavable complex"[5](https://pubmed.ncbi.nlm.nih.gov/11193884/) • [6](https://www.nature.com/articles/nrc1977) |
| Cytotoxic mechanism | S-phase-specific killing through potentially lethal collisions between advancing replication forks and topo-I cleavable complexes; collisions with transcription machinery also contribute[5](https://pubmed.ncbi.nlm.nih.gov/11193884/) |
| Chemical liability | The active lactone E-ring hydrolyzes reversibly to the carboxylate at physiological pH; the carboxylate is about 10-times less potent and binds human serum albumin with 200-fold greater affinity than the lactone[7](https://aacrjournals.org/clincancerres/article/8/3/641/289125/Current-Perspectives-on-the-Clinical-Experience) |
| Approved derivatives | Irinotecan, topotecan, and belotecan have been approved for cancer treatment, despite several thousand synthesized derivatives[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC5752681/) • [18](https://pmc.ncbi.nlm.nih.gov/articles/PMC11186875/) |
| Stereochemistry | The naturally occurring 20S-isomer inhibits purified topoisomerase I 10 to 100 times more potently than the 20R-isomer[7](https://aacrjournals.org/clincancerres/article/8/3/641/289125/Current-Perspectives-on-the-Clinical-Experience) |
| Main limitations | Poor water solubility, rapid lactone hydrolysis, dose-limiting diarrhea and neutropenia, and resistance mediated partly by ABCG2 and ABCC1 efflux transporters[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC2707511/) |
## Structure and chemistry
Camptothecin is a planar pentacyclic quinoline alkaloid. Its five-ring system comprises a quinoline portion (rings A and B), a pyrrolidine ring, a lactam (ring D), and a terminal α-hydroxy-δ-lactone ring (E) bearing a chiral center at position C-20 with the (S) configuration.[1](https://www.sciencedirect.com/science/article/pii/S0960894X16313646) • [7](https://aacrjournals.org/clincancerres/article/8/3/641/289125/Current-Perspectives-on-the-Clinical-Experience) The A and B rings tolerate substitution at positions 7, 9, 10, and 11 while retaining or improving activity, whereas altering the C and D rings inactivates the molecule; the E-ring lactone is required for activity because it participates in binding to topoisomerase I, and hydrolysis or removal of the lactone abolishes all activity.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/)
**Lactone instability.** The E-ring lactone undergoes spontaneous, reversible, pH-dependent hydrolysis: the intact lactone predominates at acidic pH and the ring-opened carboxylate at neutral and alkaline pH.[7](https://aacrjournals.org/clincancerres/article/8/3/641/289125/Current-Perspectives-on-the-Clinical-Experience) The carboxylate form has superior water solubility but is about 10-times less potent than the lactone, and it binds human serum albumin tightly, depleting the active lactone from the bloodstream; in human serum the lactone is converted to the carboxylate within minutes at physiological pH.[7](https://aacrjournals.org/clincancerres/article/8/3/641/289125/Current-Perspectives-on-the-Clinical-Experience) • [9](https://pmc.ncbi.nlm.nih.gov/articles/PMC2707511/) One review reports a half-life of 11 minutes for this conversion, with only 5.3% of total camptothecin remaining in the lactone form.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC12655487/) Substituents on the A and B rings modulate albumin binding and thus the lactone-carboxylate equilibrium in plasma; the lactone form of the active metabolite SN-38 preferentially binds albumin, shifting the equilibrium toward the active form.[7](https://aacrjournals.org/clincancerres/article/8/3/641/289125/Current-Perspectives-on-the-Clinical-Experience)
## Mechanism of action
DNA topoisomerase I relaxes supercoiled DNA by making a transient single-strand break, covalently linking the enzyme to the 3' end of the nicked strand, and then religating.[12](https://pubmed.ncbi.nlm.nih.gov/10846537/) Camptothecin binds at the interface of the topoisomerase I-DNA complex and blocks the rejoining step, causing accumulation of the covalent cleavable complex; because the drug binds this interface, camptothecins are described as a paradigm for interfacial inhibitors that reversibly trap macromolecular complexes.[5](https://pubmed.ncbi.nlm.nih.gov/11193884/) • [6](https://www.nature.com/articles/nrc1977)
The drug-trapped complexes kill cells mainly when advancing replication forks collide with them, converting the single-strand lesion into double-strand breaks; the killing is therefore S-phase-specific.[5](https://pubmed.ncbi.nlm.nih.gov/11193884/) • [12](https://pubmed.ncbi.nlm.nih.gov/10846537/) Collisions with the transcription machinery also form long-lived covalent topo-I DNA complexes that contribute to cytotoxicity.[5](https://pubmed.ncbi.nlm.nih.gov/11193884/) Cells respond to this damage with two repair pathways involving covalent modification of topoisomerase I: ubiquitin/26S proteasome-mediated degradation of the enzyme, and SUMO conjugation.[5](https://pubmed.ncbi.nlm.nih.gov/11193884/)
## Clinical derivatives
The parent compound's poor solubility and unpredictable toxicity limited its early therapeutic development, and clinical trials of camptothecin itself were halted.[13](https://pubmed.ncbi.nlm.nih.gov/9358934/) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/) Interest revived in the late 1980s when topoisomerase I was identified as the molecular target, and water-soluble analogs were developed by adding solubilizing groups to the quinoline ring.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/) • [13](https://pubmed.ncbi.nlm.nih.gov/9358934/)
**Irinotecan (CPT-11)** is a prodrug with an ethyl substituent at position 7 and a dipiperidyl carbamate at position 10; it is metabolized by human carboxylesterase 2 and hepatic enzymes to SN-38, a 7-ethyl-10-hydroxy derivative that is 100 to 1000 times more cytotoxic than the prodrug.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/) It is used for metastatic colorectal cancer.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/) **Topotecan** owes its solubility to a tertiary amine at the 9-position and has been approved for ovarian, cervical, and small cell lung cancer.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/) Other analogs, including 9-aminocamptothecin, gimatecan, belotecan, lurtotecan, and exatecan, have been studied clinically.[13](https://pubmed.ncbi.nlm.nih.gov/9358934/) • [14](https://www.cancer.gov/grants-training/training/resources-trainees/courses-fellowships/2022-topoisomerase) The dose-limiting side effects of the class are diarrhea and neutropenia.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC2707511/)
## Resistance
Resistance to camptothecin-based drugs limits their clinical success. Preclinical studies point to several contributing mechanisms: inadequate drug accumulation in the tumor, high drug efflux, mutations in TOP1 that prevent CPT docking, altered signaling from the drug-TOP1-DNA complex, expression of [DNA repair](https://www.edgepedia.org/dna-repair) proteins, and failure to activate cell death pathways.[15](https://www.sciencedirect.com/science/article/pii/S0304419X12000650) Camptothecins are not substrates of ABCB1 ([P-glycoprotein](https://www.edgepedia.org/p-glycoprotein)), but both ABCC1 and the half-transporter ABCG2 mediate resistance in cultured cells, and cells overexpressing these transporters are cross-resistant to camptothecins.[16](https://karger.com/pha/article-pdf/81/4/275/3420439/000115967.pdf) • [9](https://pmc.ncbi.nlm.nih.gov/articles/PMC2707511/) The DNA repair proteins tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly([ADP-ribose](https://www.edgepedia.org/adp-ribose)) polymerase (PARP) have been examined as predictive markers and therapeutic targets for combination strategies.[17](https://pubmed.ncbi.nlm.nih.gov/22788763/)
## Strategies to overcome the limitations
[Medicinal chemistry](https://www.edgepedia.org/medicinal-chemistry) has attacked the E-ring instability directly. Homocamptothecins enlarge the E-ring by one carbon atom to a seven-membered β-hydroxylactone, which opens less readily but cannot reclose once opened; diflomotecan is the clinical derivative of this approach.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC2707511/) Delivery-focused strategies include macromolecular and polymer constructs that covalently append or non-covalently associate camptothecin to improve solubility and lactone stability while exploiting tumor physiology to raise tumor exposure and lower systemic toxicity, as well as nanoemulsions, lipid systems, and antibody-drug conjugates carrying CPT-type payloads.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/) • [11](https://pmc.ncbi.nlm.nih.gov/articles/PMC12655487/)
Despite several thousand synthesized derivatives, no new camptothecin beyond irinotecan and topotecan has been approved for cancer treatment, and some reviewers argue that new Top1-inhibiting CPTs are unlikely to prove significantly better than those two drugs in overall antitumor activity and toxicity; they point instead to CPT analogs with novel mechanisms that target cancer survival-associated proteins such as survivin, Mcl-1, and XIAP independently of Top1 inhibition.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC5752681/)
## References
1. [The long story of camptothecin: From traditional medicine to drugs, ScienceDirect](https://www.sciencedirect.com/science/article/pii/S0960894X16313646)
2. [Camptothecin, MeSH, NCBI](https://www.ncbi.nlm.nih.gov/mesh/68002166)
3. [Tree Extract Acts Against Cancer, JAMA 1966;197(10):45](https://jamanetwork.com/journals/jama/article-abstract/661161)
4. [Kohn, Drugs Against Cancer, Chapter 11: The Topoisomerase I Story, NCI](https://discover.nci.nih.gov/kohn/book/drugs_against_cancer_chapter11_v220928br3.pdf)
5. [Liu LF et al., Mechanism of action of camptothecin, Ann N Y Acad Sci 2000](https://pubmed.ncbi.nlm.nih.gov/11193884/)
6. [Topoisomerase I inhibitors: camptothecins and beyond, Nature Reviews Cancer](https://www.nature.com/articles/nrc1977)
7. [Current Perspectives on the Clinical Experience, Pharmacology, and Continued Development of the Camptothecins, Clinical Cancer Research](https://aacrjournals.org/clincancerres/article/8/3/641/289125/Current-Perspectives-on-the-Clinical-Experience)
8. [Camptothecin (CPT) and its derivatives... did we miss something in CPT analogue molecular targets? PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5752681/)
9. [DNA Topoisomerase I Inhibitors: Chemistry, Biology and Interfacial Inhibition, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2707511/)
10. [Cancer Therapies Utilizing the Camptothecins: A Review of in Vivo Literature, Mol Pharm 2010, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3733266/)
11. [Camptothecin in Cancer Therapy: Current Challenges and Emerging Strategies with Nanoemulsions, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12655487/)
12. [Pharmacology of camptothecin and its derivatives, PubMed](https://pubmed.ncbi.nlm.nih.gov/10846537/)
13. [Topoisomerase I inhibitors: review and update, PubMed](https://pubmed.ncbi.nlm.nih.gov/9358934/)
14. [Camptothecin and its derivatives used for the treatment of cancers, NCI](https://www.cancer.gov/grants-training/training/resources-trainees/courses-fellowships/2022-topoisomerase)
15. [Tomicic MT, Kaina B. Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors, BBA Reviews on Cancer 2013](https://www.sciencedirect.com/science/article/pii/S0304419X12000650)
16. [Pharmacology review, Karger](https://karger.com/pha/article-pdf/81/4/275/3420439/000115967.pdf)
17. [DNA repair and resistance to topoisomerase I inhibitors: mechanisms, biomarkers and therapeutic targets, PubMed](https://pubmed.ncbi.nlm.nih.gov/22788763/)
18. [pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11186875/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Enzyme classes and activities › DNA and RNA processing enzyme activities › Topoisomerases › Topoisomerase inhibitors and poisons*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license