Camptothecin (CPT) is a plant alkaloid isolated from Camptotheca acuminata. Initial studies showed that CPT displayed potent antitumor activity against a wide range of tumors, but the drug was discontinued because of toxic side effects. There was a renewed interest in CPT when subsequent findings identified the enyzme, topoisomerase I (topo I), as the main molecular target. Since CPT was the only known drug to target topo I, finding less toxic and more water soluble CPT derivatives became a subject of numerous investigations.Topotecan (TPT) and Irinotecan (CPT-11) are two water soluble CPT derivatives that are currently being used for the treatment of human cancers. CPT-11 has been used in the treatment of colon, breast, gastric and small-cell lung cancers as well as leukemia, whereas topotecan has been used against recurrent small cell lung cancer, ovarian cancer and endometrial cancer. CPT-11 must be converted to the active compound, SN-38 (7-ethyl-10 hydroxycamptotecin B-glucuronide) by carboxylesterase. Thus, increased drug sensitivity to irinotecan correlates with carboxylesterase expression and activity. Cisplatin is also a substrate of the ABC drug transport protein, multidrug resistance related protein-3 (MRP3).CPT and its derivatives interact reversibly with a DNA-enzyme complex and have no detectable binding to isolated topo I or DNA. However, the x-ray crystal structue of human topo I-DNA-topotecan ternary complex shows that topotecan can mimic a DNA base pair. These findings may partially explain how topotecan can intercalate in DNA in the absense of topo enzyme in some instances. In the presence of camptotecins, topo I is unable to reseal nicked DNA because the drug blocks the active site of the covalently bound enzyme. However, single strand DNA breaks aone are not sufficient for cell death to occur and instead must be converted into permanent DNA double strand breaks by collicsion with the moving replication fork. Conversely, it has also been reported that CPT induced DNA strand-breaks can occur in unstimulated leukocytes where little or nor replication is occurring, and thus other cellular events besides the collision of cleavable complexes with replication forks may have a role in CPT induced DNA damage. The molecular basis of CPT induced cell death is not completely understood, since topo I cleavable complexes are readily reversible after drug removal. It is generally accepted that collision of the moving replication fok with the topo I cleavable complexes leads to three biochemical events, formation of a double-strand DNA break, irreversible arrest of the replication fork, and formation of an irreversible topo I-linked DNA break. It is thought that one or more of these events initiates S-phase cell death and G2 phase cell cycle arrest.