Multitargeted
tyrosine kinase inhibitors (TKI)
axitinib,
pazopanib, and
sunitinib are used to treat many solid
tumors. Combination trials of TKIs with
gemcitabine, a
nucleoside anticancer
drug, in pancreas, renal, lung, ovarian, and other
malignancies resulted in little benefit to patients. TKI interactions with human
nucleoside transporters (hNT) were studied by assessing inhibition of [(3)H]
uridine uptake in yeast producing recombinant hNTs individually and in cultured human
cancer cell lines.
Axitinib,
pazopanib, and
sunitinib inhibited hENT1 at low micromolar concentrations. In A549, AsPC-1, and Caki-1 cells, [(3)H]
uridine, [(3)H]
thymidine, [(3)H]
gemcitabine, and [(3)H]fluorothymidine (FLT) accumulation was blocked by all three TKIs.
Pazopanib >
axitinib ≥
sunitinib inhibited hENT1 with IC50 values of 2, 7, and 29 μmol/L, respectively, leading to reduced intracellular
gemcitabine and FLT accumulation. Pretreatment or cotreatment of Caki-1 cells with TKIs reduced cellular accumulation of [(3)H]
nucleosides, suggesting that TKI scheduling with
nucleoside drugs would influence cytotoxicity. In combination cytotoxicity experiments that compared sequential versus simultaneous addition of drugs in Caki-1 cells, cytotoxicity was greatest when
gemcitabine was added before TKIs. In clinical settings, TKI inhibitor concentrations in
tumor tissues are sufficient to inhibit hENT1 activity, thereby reducing
nucleoside chemotherapy drug levels in
cancer cells and reducing efficacy in combination schedules. An additional unwanted interaction may be reduced FLT uptake in
tumor tissues that could lead to aberrant conclusions regarding
tumor response.