Camptothecin is a plant alkaloid derived from the Camptotheca acuminata tree. The camptothecins act primarily by inhibition of the topoisomerase I enzyme.[1-4] Once bound to the topoisomerase I-DNA complex, the camptothecins block reannealing of the parent DNA, thereby halting nucleic acid synthesis in the cell, leading to cell death.[2-4] Camptothecin sodium was originally evaluated and found active in the late 1960s but demonstrated intolerable toxicities, including diarrhea, myelosuppression, and hemorrhagic cystitis.[5,6]
More recently, irinotecan (Camptosar), a semisynthetic, water-soluble derivative of camptothecin, was found to have more tolerable and predictable toxicity, as well as heightened in vitro and in vivo antitumor activity. Myelosuppression (mainly neutropenia) and diarrhea continue to be dose-limiting toxicities; yet in US studies, grade 3 or 4 leukopenia or severe diarrhea occur in only one quarter of patients. Nausea, vomiting, anorexia, abdominal pain, alopecia, fatigue, fever, pneumonitis, and hemorrhage may be seen. Elevation of serum creatinine, amylase, and liver function values have also been observed.
Irinotecan (CPT-11) is converted by carboxylesterases to its more active metabolite, SN-38, in the liver. In vitro, SN-38 is 250- to 1,000-fold more active an inhibitor of topoisomerase I activity than is irinotecan. The mean terminal half-life of SN-38 in plasma is slightly longer than that of irinotecan (11.5 ± 3.8 vs 6.3 ± 2.2 hours). The time to peak concentration of SN-38 is highly interpatient-dependent, occurring 30 to 90 minutes after the end of the infusion. Murine studies suggest that the liver may concentrate irinotecan, convert it to SN-38, and eliminate both compounds, as well as the glucuronide conjugate of SN-38, via biliary excretion. Renal clearance has not been reported to be a major route of elimination for these compounds in humans.
Several phase I and II studies conducted in Japan, France, and the United States have demonstrated antitumor activity of irinotecan in several tumor types. Irinotecan has been approved for clinical use in Japan for small-cell lung cancer, non-small-cell lung cancer, and uterine and cervical cancers. In the United States, irinotecan is approved for the treatment of fluorouracil (5-FU)-refractory colon cancer.
Kawato et al demonstrated the antitumor activity of irinotecan and SN-38 in human gastric adenocarcinoma SC-6 and St-15 xenografts. In these cell lines, irinotecan and SN-38 produced superior responses compared with responses produced by doxorubicin and 5-FU. More recently, Mitsui et al confirmed the activity of irinotecan and SN-38, while demonstrating the superiority of DX-8951f, another camptothecin derivative, against four human gastric cancer cell lines. Antitumor activity of irinotecan (and DX-8951f) was again noted in human gastric adenocarcinoma SC-6 xenografts.
Irinotecan remains an investigational drug in esophageal cancer. As yet, no formal phase I or II studies have been reported, however, some preclinical data suggest significant activity. Ikeda et al examined the antitumor activity of four camptothecin analogs--DX-8951f, SN-38, 9-aminocamptothecin, and topotecan (Hycamtin)--against six human esophageal cancer cell lines. The authors noted significant antitumor activity of all four analogs, especially DX-8951f. In addition, the cell lines all expressed high levels of topoisomerase I, the target of these camptothecin compounds.
1. Chen AY, Liu LF: DNA topoisomerases: Essential enzymes and lethal targets. Ann Rev Pharmacol Toxicol 34:191-218, 1994.
2. Hsiang YH, Hertzberg R, Hecht S: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14,873-878, 1985.
3. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1,722-726, 1988.
4. Creemers CJ, Lund B, Verwij J: Topoisomerase I inhibitors: Topotecan and irinotecan. Cancer Treat Rev 20:73-96, 1994.
5. Wall ME, Wani MC, Cook CE: Plant antitumor agents: I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 88(3):888-890, 1966.
6. Gottleib JA, Guarino AM, Call JB: Preliminary and pharmacologic and clinical evaluation of camptothecin sodium. Cancer Chemother Rep 54:461-470, 1970.
7. Tsuji T, Kaneda N, Kado K: CPT-11 converting enzyme from rat serum: Purification and some properties. J Pharmacobiodyn 14:341-349, 1992.
8. Rothenberg ML, Kuhn JG, Burris HAI: Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11:2194-2204, 1993.
9. Kawato Y, Aonuma M, Hirota Y: Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the anti-tumor effect of CPT-11. Cancer Res 51:4187-4191, 1991.
10. Mitsui I, Kumazawa E, Hirota Y: A new water soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res 86:776-782, 1995.
11. Ikeda K, Terashima M, Yqegashi Y: Antitumor activities of camptothecin analogs against human esophageal cancer. Proc Am Assoc Cancer Res 36:2702, 1995.
12. Masumoto N, Nakano S, Esaki T: Inhibition of cis-diamminedichloroplatinum (II)- induced DNA interstrand cross-link removal by 7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous-carcinoma cells. Int J Cancer 62:70-75, 1995.
13. Masumoto N, Nakano S, Esaki T: Sequence-dependent modulation of anticancer drug activities by 7-ethyl-10-hydroxycamptothecin in an HST-1 human squamous carcinoma cell line. Anticancer Res 15:405-410, 1995.
14. Masuda N, Fukuoka M, Kudoh S: Phase I study of irinotecan and cisplatin with granulocyte colony-stimulating factor support for advanced non-small-cell lung cancer. J Clin Oncol 12:90-96, 1994.
15. Masuda N, Fukuoka M, Kudoh S: Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer. Br J Cancer 68:777-782, 1993.
16. Mori K, Suga U, Kishiro I: A phase I study of CPT-11 and cisplatin (5 day continuous infusion) for advanced non-small-cell lung cancer. Proc Am Soc Clin Oncol 13:366, 1994.
17. Nitta T, Takada M, Hirashima T: Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer. Proc Am Assoc Cancer Res 34:206, 1993.
18. Kambe M, Wakui A, Nakao I, et al: A late phase II study of irinotecan (CPT-11) in patients with advanced gastric cancers. Proc Am Soc Clin Oncol 12:584, 1993.
19. Shirao K, Shimada Y, Kondo H, et al: Phase I-II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 15:921-927, 1997.
20. Boku N, Ohtsu Y, Shimada K, et al: Phase II study of a combination of CDDP and CPT-11 in metastatic gastric cancer: CPT-11 study group for gastric cancer. Proc Am Soc Clin Oncol 16:936, 1997.
21. Saltz L, Kanowitz J, Kelsen D, et al: Phase I study of weekly cisplatin (CDDP) plus irinotecan (CPT-11) in patients (PTS) with advanced solid tumors. Proc Am Soc Clin Oncol 15:1540, 1996.
22. Rowinsky E, Gilbert M, McGuire W, et al: Sequences of Taxol and cisplatin: A phase I and pharmacologic study. J Clin Oncol 9:1692-1703, 1991.
23. Frasci G, Comella P, Parziale A, et al: Cisplatin-paclitaxel weekly schedule in advanced solid tumors: Phase I study. Ann Oncol 8:291-293, 1997.
24. Couteau C, Lokiec F, Vernillet L, et al: Phase I dose-finding and pharmacokinetic (PK) study of docetaxel (D) in combination with irinotecan (I) in advanced solid tumors. Proc Am Soc Clin Oncol 16:709, 1997.
25. Debernardis D, Cimoli G, Parodi S, et al: Interactions between Taxol and camptothecin. Anticancer Drug Des 7:531-534, 1996.
26. Lilenbaum R, Ratain M, Miller A, et al: Phase I study of paclitaxel and topotecan in patients with advanced tumors: A Cancer and Leukemia Group B study. J Clin Oncol 13:2230-2237, 1995.
27. Saltz L, Kanowitz J, Kemeny NE, et al: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 14:2959-2967, 1996.