Drug resistance remains a significant impediment to successful
chemotherapy and constitutes a major prognostic factor in
osteosarcoma (OS) patients. This study was designed to identify the role and prognostic significance of multidrug-resistance (MDR)-related transporters, such as
multidrug resistance protein 1 (MDR1),
multidrug-resistance-associated protein (
MRP1) and
breast-cancer-related
protein (BCRP), in OS using cationic lipophilic radiotracers. We evaluated the chemosensitivity of four OS cell lines (Saos-2, 143B,
MNNG/HOS and U-2OS) to
doxorubicin (DOX),
cisplatin (CIS) and
methotrexate. The expression of MDR-related transporters was analyzed at
mRNA level by quantitative polymerase chain reaction and at functional level by
99mTc sestamibi and 99mTc tetrofosmin. The effectiveness of MDR modulators [
cyclosporin A (CsA) and
imatinib] on transporter inhibition and on the reversal of resistance was also assessed.
MNNG/HOS and U-2OS cells expressing high levels of MDR1 were highly resistant to DOX and showed reduced accumulation and higher efflux for radiotracers. Although
MRP1 was uniformly expressed in all cells, only U-2OS was resistant to CIS. CsA restored sensitivity to DOX and CIS, and enhanced the accumulation and efflux half-life of radiotracers in MDR1-expressing cell lines. The chemosensitivity of OS cells to DOX was strongly dependent on
mRNA MDR1 expression and could be circumvented by adding CsA. The kinetic parameters of radiotracers correlated with MDR1 expression levels, hence predicting DOX resistance. We concluded that sensitivity to
chemotherapy is strongly dependent on the expression of MDR1 transporter and that radiotracer studies could prove clinically useful in predicting
chemotherapy response and in evaluating the efficacy of MDR-reversing agents.