Studies Linking NT Function to Drug Sensitivity and Clinical Outcome in Cancer Patients

Studies Linking NT Function to Drug Sensitivity and Clinical Outcome in Cancer Patients 

Evidence obtained from in vitro studies (cultured cell models) clearly suggests that NTs contribute to nucleoside-derived drug cytotoxicity. Nevertheless, key issues are to determine whether these findings can be transferred to clinical settings and whether they will help to understand what roles NT proteins actually play in tumor responsiveness to nucleoside-based therapies. However, the lack, until recently, of suitable molecular tools such as isoform-specific anti-NT antibodies and the difficulty to obtain and analyze tumor samples have delayed this approach. Clinical studies suggesting a link between NT expression and drug sensitivity are summarized in Table 2.2. 

Most ofthe clinical and ex vivo studies have focused on the hENTl transporter in lymphoproliferative malignancies because hENTl is the most abundant and widely distributed NTs in mammalian cells. Moreover, its abundance could be measured in the absence of suitable antibodies by high-affinity binding of NBTI or fluorescent nucleoside derivative SAENTA. The number of ENTl transporters determined by NBTI binding in acute myeloid and lymphoid leukemia (AML and ALL) cells exhibited interpatient variation and correlated with intracellular accumulation of the cytarabine metabolite ara-CTP [124]. Similarly, Gati et al. demonstrated a correlation between the expression of hENTl and the in vitro sensitivity to cytarabine and fiudarabine of blasts from acute leukemia patients [125, 138]. In contrast. 

Transporter Detection method Disease Drug Correlation Reference 

Abbreviations HD Hodgkin disease ara-C citarabine 2-CdA cladribine Fara-A fiudarabine dFdC gemcitabine CMF cyclophosphamide-methotrexate-5-fiuorouracil. + positive correlation — negative correlation ns no significative correlation. 

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