Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2010 Apr 5;7(2):307-49.
doi: 10.1021/mp900243b.

Cancer therapies utilizing the camptothecins: a review of the in vivo literature

Vincent J Venditto  1 , Eric E Simanek
Affiliations
Review

Cancer therapies utilizing the camptothecins: a review of the in vivo literature

Vincent J Venditto et al. Mol Pharm. .

Abstract

This review summarizes the in vivo assessment-preliminary, preclinical, and clinical-of chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and hydrolysis under physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity. Binding inhibits DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or noncovalently associated with the goal of improving solubility and lactone stability, while taking advantage of the tumor physiology to deliver larger doses of drug to the tumor with lower systemic toxicity. With the increasing interest in drug delivery and polymer therapeutics, additional constructs are anticipated. The goal of this review is to summarize the relevant literature for others interested in the field of camptothecin-based therapeutics, specifically in the context of biodistribution, dosing regimens, and pharmacokinetics with the desire of providing a useful source of comparative data. To this end, only constructs where in vivo data is available are reported. The review includes published reports in English through mid-2009.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Quinoline modified camptothecin derivatives.
Figure 2
Figure 2
Diflomotecan and related modified camptothecins.
Figure 3
Figure 3
Amino acid linked 20-hydroxy ester of camptothecin.
Figure 4
Figure 4
NK012 showing 12 kDa PEG block and 7 kDa poly(L-glutamic acid) block with 20 wt% overall SN-38.
Figure 5
Figure 5
Pegamotecan made using 40 kDa PEG-diacid with two camptothecin moieties attached through alanine linker.
Figure 6
Figure 6
IT-101 with a 3.4 kDa PEG chain and overall molecular weight of 85 kDa.
Figure 7
Figure 7
Phthalmide polymers with molecular weight of 25.5 kDa.
Figure 8
Figure 8
PLGA polymer with glycine linker to CPT containing 37 wt% drug in a 49 kDa polymer.
Figure 9
Figure 9
HPMA polymer with a GlyPheLeuGly linker or a Gly-hexanoic acid-Gly linker (MAG-CPT) to CPT with 10 wt% drug in a 21 kDa polymer.
Figure 10
Figure 10
T-0128 polymer conatining SN-38 linked with glycine and propanolamine to a 130 kDa polymer with 3 wt% drug loading and 0.5 carboxylates per sugar.
Figure 11
Figure 11
Carboxymethyl dextran polyalcohol polymers. DE-310 containing 5–7 wt% exatecan in a 360 kDa polymer with 0.4 carboxylates per sugar. XMT-1001 containing 5–7 wt% camptothecin in a 70kDa polymer with 0.2 carboxylates per sugar.
Figure 12
Figure 12
EZN-2208 is a 40 kDa four arm PEG with four SN-38 moieties attached.
Figure 13
Figure 13
Poly(L-lysine) dendrimer containing eight CPT and eight PEG5000 chains.
Figure 14
Figure 14
Compounds investigated for human serum albumin linked CPT conjugates.
Figure 15
Figure 15
Ideal structures of PEG-CPT constructs containing LHRH or LHRH and BH3 antiapoptotic peptide.
Figure 16
Figure 16
SN-38 linked to Vectocell cell penetrating peptide, through a maleimide linkage.
Scheme 1
Scheme 1
Camptothecin in the lactone form and open carboxylate from.
See this image and copyright information in PMC

References

    1. Wall ME, Wani MC, Cooke CE, Palmer KH, McPhail AT, Sim GA. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc. 1966;88:3888–3890.
    1. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agentsVI The isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia. J Am Chem Soc. 1971;93:2325–2327. - PubMed
    1. Slichenmyer WJ, Von Hoff DD. New natural products in cancer chemotherapy. J Clin Pharmacol. 1990;30:770–788. - PubMed
    1. Wall ME. Camptothecin and taxol: discovery to clinic. Med Res Rev. 1998;18:299–314. - PubMed
    1. Hsiang Y-H, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem. 1985;260:14873–14878. - PubMed

Publication types