Differential activity of topotecan, irinotecan and SN-38 in fresh human tumour cells but not in cell lines.
The topoisomerase I inhibitors topotecan irinotecan (CPT-11) and its metabolite SN-38 were studied in a panel of cell lines and in primary tumour cells from patients, using a non-clonogenic cytotoxicity assay. All three substances showed similar activity patterns in the panel of cell lines established to classify the drugs mechanistically. In the patient tumour cells the drugs had different effects. In haematological and ovarian cancer samples, SN-38 was much more potent than topotecan, followed by irinotecan, while in colorectal cancer samples only irinotecan showed substantial activity. This in vitro activity pattern seems to agree with clinical experiences to date. The inactivity of SN-38 in colorectal cancer suggests irinotecan may also have some other role in addition to being a prodrug to SN-38. This study raises questions as to the role and relevance of early preclinical model systems in anticancer drug development, and suggests that important information can be obtained from studies using primary cultures of human tumour cells.
Jonsson
E
E
Department of Medical Sciences, Clinical Pharmacology, University Hospital, SE-751 85, Uppsala, Sweden. elin.jonsson@medsci.uu.se
Dhar
S
S
Jonsson
B
B
Nygren
P
P
Graf
W
W
Larsson
R
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005470:Fluorometry; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy*; D019772:Topotecan / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin