ZD1839 (Iressa) modifies the activity of key enzymes linked to fluoropyrimidine activity: rational basis for a new combination therapy with capecitabine.
OBJECTIVE
The efficacy of new oral fluoropyrimidines, including capecitabine, is improved in cells expressing high levels of thymidine phosphorylase (TP) and low levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase. We used a human head and neck cancer cell line (CAL33) to examine the influence of cell cycle modifications on TS, TP, and dihydropyrimidine dehydrogenase activity.


METHODS
Cells were exposed to the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa(2)) and 5'-deoxy-5-fluorouridine (5'-DFUR), alone and in combination, for up to 96 h, and modifications in cell cycle, enzyme activity, and gene expression were examined.


RESULTS
ZD1839 (24- to 72-h exposure) markedly reduced proliferation and caused a rapid increase in G(0)-G(1) and a decrease in S phase; a 40-fold decrease in TS activity at 24 h and a 2.5-fold increase in TP activity at 48 h were observed. A significant link between TP activity and expression was observed (r(2) = 0.98; P = 0.0068). Additional investigations pointed out an increased cellular production of 5-fluorouracil anabolites from 5'-DFUR when cells were preincubated with ZD1839. Dose-effect curves of ZD1839 and 5'-DFUR, alone and in combination, were examined. Combination indices for ZD1839 + 5'-DFUR were 0.58 +/- 0.1 and 0.63 +/- 0.1 for 50% survival and 25% survival, respectively. Additional investigations pointed out an increased cellular production of 5-fluorouracil anabolites from 5'-DFUR when cells were preincubated with ZD1839.


CONCLUSIONS
These data demonstrate a strong synergistic interaction between ZD1839 and 5'-DFUR when ZD1839 is applied before or concurrently with 5'-DFUR. Such a drug combination would have two advantages: (a) the theoretical advantage of tumor selectivity of epidermal growth factor receptor-targeted therapy; and (b) the practical advantage of a combination therapy that could be administered p.o.
Magné
Nicolas
N
Oncopharmacology Unit, Centre Antoine Lacassagne, 06189 Nice Cedex 2, France.
Fischel
Jean-Louis
JL
Dubreuil
Alain
A
Formento
Patricia
P
Ciccolini
Joseph
J
Formento
Jean-Louis
JL
Tiffon
Céline
C
Renée
Nicole
N
Marchetti
Sandrine
S
Etienne
Marie-Christine
MC
Milano
Gérard
G
D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D017931:DNA Primers / Q000737:chemistry; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D005467:Floxuridine / Q000627:therapeutic use*; D005472:Fluorouracil / Q000031:analogs & derivatives; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008956:Models, Chemical; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000737:chemistry*; D011799:Quinazolines / Q000008:administration & dosage*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D017931:DNA Primers; D011743:Pyrimidines; D011799:Quinazolines; D012333:RNA, Messenger; D005467:Floxuridine; D003841:Deoxycytidine; D012313:RNA; C029269:5-fluoropyrimidine; D000069287:Capecitabine; D000077156:Gefitinib; D005472:Fluorouracil; C025034:doxifluridine