Potential activity of paclitaxel, vinorelbine and gemcitabine in anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma (ATC) has a rapidly fatal course in the mostly elderly patients with a median survival after diagnosis of 4-12 months. Activity of commonly used chemotherapy (doxorubicin) is low, thus more active compounds need to be introduced into the therapeutic concept of ATC. Recently, based on preclinical data Ain et al. conducted a clinical phase II study with paclitaxel 96 h infusion in ATC achieving a promising response rate of 53%. To further improve therapeutic options in ATC, we evaluated the activity of topotecan, oxaliplatin, vinorelbine, gemcitabine and paclitaxel in comparision to cisplatin and doxorubicin (1 and 96 h drug exposure) alone or in combination in the ATC cell lines SW1736 and 8505C. IC50 values were determined by the sulforhodamine B assay, potential clinical activity was estimated by relative antitumor activity (RAA) and drug interaction was analyzed using a parametric response surface approach (Greco model) of the Loewe additivity. Duration of drug effect was estimated by regrowth kinetics. We found paclitaxel, vinorelbine and gemcitabine active in ATC with RAA (1 h drug exposure) ranging from 86 to 454, 15 to 17 and 31 to 140, respectively. The activity of doxorubicin and cisplatin was moderate with RAA ranging from 1.4 to 2.2 and 0.2 to 0.3, respectively. Combined drug exposure of gemcitabine/paclitaxel and gemcitabine/vinorelbine was synergistic with a Loewe index > 0. However, these results did not reach statistical significance with p > 0.05. At clinically relevant drug concentrations paclitaxel, gemcitabine and vinorelbine but not oxaliplatin exerted a sustained growth inhibition after cessation of drug exposure for the complete assay time of 15 days. In conclusion, paclitaxel, gemcitabine and vinorelbine but not topotecan or oxaliplatin appeared to be active in anaplastic thyroid carcinoma based on RAA or growth delay at clinically relevant drug concentrations. Combinations of vinorelbine/gemcitabine and paclitaxel/gemcitabine exerted a trend to synergy. Thus, further evaluation of paclitaxel, vinorelbine and gemcitabine alone or in combination with ATC seems warranted.
Voigt
W
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Department of Hematology/Oncology, Martin Luther University, Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle/Saale, Germany. haematologie@medizin.uni-halle.de
Kegel
T
T
Weiss
M
M
Mueller
T
T
Simon
H
H
Schmoll
H J
HJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D019772:Topotecan / Q000494:pharmacology; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D014747:Vinblastine; D019772:Topotecan; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin; D000077235:Vinorelbine; D000093542:Gemcitabine