Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults.
OBJECTIVE
The fluoropyrimidine carbamate (capecitabine) is converted to 5-fluorouracil (5-FU) by thymidine phosphorylase (TP) inside target tissues. 5-FU interferes with DNA synthesis by blocking thymidylate synthase (TS) but is inactivated by dihydropyrimidine dehydrogenase (DPD). Favorable enzyme profiles (high TP and low DPD) generate high intratumor levels of 5-FU that are effective against many tumors, especially those with low TS. Capecitabine has not been tested against thyroid cancers, and it is not known to what extent thyroid cancers express TP, TS or DPD.


METHODS
To test this, we determined TP, TS and DPD in 19 thyroid cancers from young patients (14 papillary, 4 follicular, 1 medullary) by immunohistochemistry. After approval by the Human Use Committee, the intensity of TP, TS, and DPD staining was determined by two independent examiners and graded (absent=0 to intense=3) with >90% concordance.


RESULTS
TS was detected in 7/19 cancers (37%), TP in 14/19 cancers (74%) and DPD in 14/19 cancers (74%). In six tumors, TP was more intense that DPD, suggesting capecitabine sensitivity. Only five tumors failed to express TP but four of these expressed DPD, suggesting capecitabine resistance. Overall, 6/19 tumors (32% of the total) had a favorable expression profile, and all of them were papillary cancers.


CONCLUSIONS
We conclude that the majority of differentiated thyroid cancers (74%) express TP and low levels of TS (63% undetectable). The results support the hypothesis that capecitabine is activated in the majority of differentiated thyroid cancers and that 32% have favorable expression of all three enzymes (TP, TS, and DPD).
Patel
Aneeta
A
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Pluim
Thomas
T
Helms
Amy
A
Bauer
Andrew
A
Tuttle
R Michael
RM
Francis
Gary L
GL
D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000069287:Capecitabine; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000201:enzymology*; D002648:Child; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D013939:Thymidine Phosphorylase / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology*
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil