Longitudinal Time-Dependent Effects of Irradiation on Multidrug Resistance in a Non–Small Lung Cancer Cell Line

Abstract

Multidrug resistance (MDR) in cancer is known to decrease the therapeutic efficacy of chemotherapy. The effects of irradiation on MDR in cancer cells remain unclear. Tc-99m methoxyisobutylisonitrile (MIBI) exhibits the same ATP-binding cassette (ABC) transporter kinetics as the chemotherapeutic compound doxorubicin. In this study, we investigated the synergistic effects of chemotherapeutics and irradiation [0 Gy: C (control) group; 3, 6, 9, 12 Gy: I (irradiation) group] in the human non-small lung cancer cell line H1299 exhibiting MDR, on MIBI and doxorubicin ABC transporter kinetics, in vitro and in vivo, respectively. In vitro, inhibition of H1299 cell proliferation by irradiation was found to be irradiation dose dependent. The degree and duration of MDR inhibition in vitro in H1299 were also dose dependent. In the cells of both the C group and 3-Gy I group, no significant difference of MIBI accumulation was observed. In the 6-Gy I group, a higher MIBI accumulation was observed at only 7 days after irradiation relative to the C group. A higher MIBI accumulation in the 9-and 12-Gy I groups with a significant difference from the C group was observed at 4 to 14 days after irradiation. A significant negative correlation between intracellular MIBI accumulation and cell replication was found. In vivo, high accumulation and retention of doxorubicin were observed in irradiated tumors in the H1299 xenograft mice group at 4 to 14 days after 9-Gy irradiation compared with the control mice group. These results provide evidence for a synergistic effect of concurrent chemotherapy and radiotherapy. Mol Cancer Ther; 13(11); 2706-12. Ó2014 AACR.

Efficacy of Combination Therapy with Lenvatinib and Radioactive Iodine in Thyroid Cancer Preclinical Model

“…A modified protocol as previously described was used for iodide accumulation studies [ 34 ]. Briefly, K1, FTC-133, or K1-NIS cells treated with vehicle (0.1% DMSO in media) or 3 and 20 μM lenvatinib mesilate (lenvatinib; supplied from Eisai Co., Ltd., Tokyo, Japan) for 48 h were harvested using Accutase (Innovative Cell Technologies, Inc., California, USA, AT-104) and suspended in 7.0 mL of complete medium at a concentration of 1–2 × 10 6 cells/mL.…”

“…The intracellular accumulation ratio (CPMin/CPMout) was calculated as the ratio of radioactivity concentration inside the cell to that found in the supernatant. The accumulation ratio equation was calculated as follows using the radioactivity measurements in cell pellets and a standard representing the supernatant concentration together with an independent cell volume measurement [ 34 ]: where counts per minute pellet is the measured radioactivity rate of the pellet, counts per minute supernatant is the measured radioactivity rate of the supernatant, volume pellet = volume supernatant = 300 μL, and #cells pellet = volume pellet × density pellet = 300 μL × (3.1, 2.8, or 3.3 × 10 5 cells/μL)*, where * is the constant density per 1 μL of packed K1, FTC-133, or K1-NIS cells, respectively. The constant density of packed cells was measured using a Packed Cell Volume Tube (Techno Plastic Products AG, Trasadingen, Switzerland, 87005).…”

An Overview of In Vitro Assays of 64Cu-, 68Ga-, 125I-, and 99mTc-Labelled Radiopharmaceuticals Using Radiometric Counters in the Era of Radiotheranostics

“…Therapies capable of interfering with the harmful action of the MDR1 gene, which produces a protein capable of blocking the entry of the chemotherapy drug into the cell (thus protecting it from its action) are being studied. Other genes overexpressed in MDR tumors are those that code for ATP-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp), multiple-resistance-associated protein 1 (MRP1) and others, in the plasma membrane [ 174 , 175 ]. The overexpression of these ABC transporters causes the energy-dependent escape of chemotherapeutic agents from the intracellular volume to the extracellular environment.…”

“…Several clinical studies have shown that MIBI is a valid predictor of chemotherapy response in non-small cell lung cancer [ 181 , 182 , 183 , 184 ]. Yumiko et al [ 175 ] used [ 99m Tc]MIBI in vitro and doxorubicin in vivo to investigate how to optimally combine chemotherapy and radiotherapy to achieve the maximum synergistic effect in chemoradiotherapy, using non-small tumor cells and irradiation. To evaluate MDR suppression after γ-ray irradiation, [ 99m Tc]MIBI accumulation was performed in an in vitro study in human NSCLC cells.…”