« Back
Camptothecin & Its Derivatives for Cancer Therapy
Poster Title: Camptothecin & Its Derivatives for Cancer Therapy
Submitted on 04 Nov 2022
Author(s): Sonia Li
Affiliations: Biopharma PEG Scientific Inc.
Poster Views: 120
View poster »

Poster Information
Abstract: Camptothecin (CPT) is a pentacycle quinoline alkaloid that was basically isolated from woody plant Camptotheca acuminata. Due to their selectivity as topoisomerase I inhibitors that trap topoisomerase I cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs.

Origin of Camptothecin
In 1966, Monreoe E. Wall and Mansukh C. Wani of the National Cancer Institute isolated a pentacyclic monoterpene alkaloid from woody plant Camptotheca acuminata distributed in Southwest China.

From 1967 to 1970, researchers found that this pentacyclic monoterpene alkaloid showed strong antitumor activity in vitro against Hela cells (a cell line of cervical cancer cells), L1210 cells (mouse lymphocytic leukemia cells) and rodents, and also showed efficacy against a variety of malignancies such as gastric cancer, rectal cancer and leukemia. This triggered a wave of scientific research on the plant Camptothecin and Camptothecin-like compounds, and more and more Camptothecin-like compounds were discovered one after another. However, for many reasons, the clinical application of camptothecin has not been effectively advanced.

In 1985, Hsiang and his colleagues discovered that camptothecin and its derivatives target Topoisomerase I and reversibly bind through the TopoI-DNA cleavable complex, forming a CPT-Topo I-DNA ternary complex that inhibits DNA replication and transcription, which in turn leads to cancer cell death. Compared with TopoII inhibitors, Topo I inhibitors are highly potent and have a broad anti-tumor spectrum, and the specific inhibition of Topoisomerase I by camptothecin has triggered a new wave of interest.


Figure 1. Pharmacological effects of camptothecin

Development of Camptothecin
Camptothecin has a planar pentacyclic ring structure, that includes a pyrrolo[3,4-β]-quinoline moiety (rings A, B and C), conjugated pyridone moiety (ring D) and one chiral center at position 20 within the alpha-hydroxy lactone ring with (S) configuration (the E-ring).


Figure 2. Strucure of camptothecin

There are three main problems in the development of camptothecin-based drugs.

▶ Due to its special structure, camptothecin has poor lipid and water solubility, thus it has poor druggability and must be modified for water solubility.
▶ Modification leads to rapid release of the drug, and excessive blood concentrations can trigger serious toxic side effects, such as diarrhea, hemorrhagic cystitis, and severe bone marrow suppression.
▶ Structural modifications need to consider the release rate and stability of the drug to ensure effectiveness with high safety.
In order to acquire low-toxic water-soluble camptothecin derivatives, certain active sites on their five-ring backbone are usually modified, such as the A, B and E rings, to improve the water solubility of camptothecin, reduce the toxic side effects and increase the stability of the lactone ring, where the most studied modification sites are the 7, 9, 10 and 20 carbon positions.

The first camptothecin derivative, 10-Hydroxycamptothecin (HCPT), was developed independently in China in the 1970s and received widespread attention due to its reliable clinical efficacy. In the 1990s, a new generation of camptothecin drugs, Topotecan (TPT) and Irinotecan (CPT-11), were successfully developed, and many similar drugs have been developed since then.


Figure 3. Chemical structure of (A) camptothecin, and its derivatives: (B) topotecan, (C) irinotecan, (D) SN-38, (E) belotecan, (F) exatecan, and (G) deruxtecan, source: reference [4]

Currently, 3 camptothecin-derived topoisomerase I inhibitors were approved worldwide. In 1996, Irinotecan (CPT-11) was approved by the FDA for the treatment of small cell and non-small cell lung cancer and cervical and ovarian cancer; in 1996, Topotecan (TPT) was approved by the FDA for the second-line treatment of small cell lung cancer and ovarian cancer; and in 2003, Belotecan (CDK-602) was approved in Korea for the treatment of small cell lung cancer and ovarian cancer (Table 1).


Table 1. Approved camptothecin-derived topoisomerase I inhibitors

Drug Delivery Technology Helps Camptothecin-derived Drugs
Drug delivery is widely used in the antineoplastic field to improve drug efficacy, reduce drug toxicity, and improve drug safety. Various technologies have been applied to overcome the problem of the bioavailability of camptothecin drugs, such as liposomes, antibody-drug conjugates, dendrimers and micelles, etc.

Irinotecan, a semisynthetic analog of the quinoline-basedalkaloid camptothecin, was first discovered and synthesized in Japan byYakult Honsha Co, Ltd, in 1983. It initially demonstrated strong activityagainst a broad variety of experimental tumors. Subsequently, clinical phaseI studies were initiated. Irinotecan was approved for the treatment of cervical, lung, and ovarian cancer in Japan in 1994. In the following years, its use was approved in Europe (1995) and the USA (1996).

Liposomal irinotecan (nal-IRI; Onivyde®; also known as pegylated liposomal irinotecan) was developed to maximize antitumor efficacy while minimizing drug-related toxicity compared to conventional (non-liposomal) formulations of this topoisomerase 1 inhibitor.


Figure 4. Liposomal irinotecan structure

Liposomes are phospholipid bilayers equipped with an internal aqueous pocket and are used as drug delivery enhancers for hydrophobic and hydrophilic drugs. Liposomes provide a protective layer that shields the encapsulated drug from structural changes or chemical degradation. In addition, the covalent adhesion of PEG molecules can be used to improve the systemic circulation of the drug.

Liposomal drugs are also being developed for belotecan and SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan after carboxylase conversion, which has a much greater activity than irinotecan in inhibiting topoisomerase I. LE-SN38 (Liposome-Entrapped SN38 ) is a SN-38 liposome developed by Neopharm. The core technology of this product is the use of tetraglyceride cardiolipin, which can closely interact with lipophilic drugs and stably embed into the liposomal phospholipid membrane, greatly improving the stability in vitro and in vivo, and also enabling the poorly soluble SN-38 to be injected for drug delivery.
Summary: Due to Camptothecin's selectivity as topoisomerase I inhibitors that trap topoisomerase I cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs.References: [1] Noura Khaiwa, Noor R. Maarouf, Mhd H. Darwish, Dima W.M. Alhamad, Anusha Sebastian, Mohamad Hamad, Hany A. Omar, Gorka Orive, Taleb H. Al-Tel,, Camptothecin's journey from discovery to WHO Essential Medicine: Fifty years of promise, European Journal of Medicinal Chemistry, Volume 223, 2021, 113639, ISSN 0223-5234,
[2] Venditto VJ, Simanek EE. Cancer therapies utilizing the camptothecins: a review of the in vivo literature. Mol Pharm. 2010 Apr 5;7(2):307-49. doi: 10.1021/mp900243b. PMID: 20108971; PMCID: PMC3733266.
[3] Fujita K, Kubota Y, Ishida H, Sasaki Y. Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. World J Gastroenterol. 2015 Nov 21;21(43):12234-48. doi: 10.3748/wjg.v21.i43.12234. PMID: 26604633; PMCID: PMC4649109.
[4] Han S, Lim KS, Blackburn BJ, et al. The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates. Pharmaceutics. 2022;14(8):1707. Published 2022 Aug 16. doi:10.3390/pharmaceutics14081707
[5] Lu Y, Park K. Po
Report abuse »
Ask the author a question about this poster.
Ask a Question »

Creative Commons