Abstract
We conducted a prospective, meaningful study of extreme low dose of 5-fluorouracil (5FU) as a metronomic agent targeting cancer associated fibroblasts (CAFs) to reverse Multidrug resistance (MDR) by sensitizing cancer associated fibroblasts and down-regulating P-glycoprotein (P-gp). The combination of 5FU and Taxol inhibited resistant KB-8-5 tumor growth by 79% and H460/Tax-R tumor growth by 55%. The inhibition was significant for both tumor types compared with Taxol treatment alone (p<0.001 and p = 0.0067, respectively). Nevertheless, the low-dose 5FU (2.2 mg/kg compared to the therapeutic dose of 50–150 mg/kg) showed negligible tumor inhibitory effect. The tumor growth inhibition study on resistant tumors demonstrated that the continuous administration of low dose 5FU with Taxol significantly inhibited the tumor growth. The treatment overcomes drug resistance in tumors by down-regulating multi-drug resistance transporter protein (P-gp), and more importantly, by eliminating CAFs recruited by resistant tumors. Compared with traditional metronomic chemotherapy, 5FU as metronomic agent targeting CAFs can avoid the disadvantages resulted from the concomitant administration of antiangiogenetic drug. The approach has good translational potential for clinical trials when treating stroma-rich drug resistant tumors.
Highlights
Multidrug resistance (MDR) is a major factor in the failure of many forms of chemotherapy [1,2]
The tumor growth inhibition study on KB-3-1 bearing nude mice demonstrated that the continuous administration of 5FU at an extremely low dose (2.2 mg/kg compared to the therapeutic dose of 50–150 mg/kg) with Taxol inhibited tumor growth by 73%
P-gp determination and α-smooth muscle actin (SMA) immunofluorescence staining clarified the relationship between P-gp expression, fibroblast levels and tumorigenesis
Summary
MDR is a major factor in the failure of many forms of chemotherapy [1,2]. Resistance to therapy has been correlated with the presence of at least one molecular ‘pump’ in tumor cell membranes, primarily P-gp, which actively expels chemotherapy drugs from the interior. While the third generation P-gp inhibitors are under development, there are no compounds currently available to ‘block’ P-gp mediated resistance in the clinic It has been demonstrated that tumor stromal cells, such as CAFs, play important roles in MDR [4,5,6], promoting tumor progression and inducing therapeutic resistance [5]. Targeting both CAFs and tumor cells using low toxicity agents could provide a novel approach and a potentially more effective treatment strategy for MDR in cancer
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