Increasing the rate of heating: a potential therapeutic approach for achieving synergistic tumour killing in combined hyperthermia and chemotherapy.
OBJECTIVE
A synergistic cancer cell killing effect of sub-lethal hyperthermia and chemotherapy has been reported extensively. In this study, in vitro cell culture experiments with a uterine cancer cell line (MES-SA) and its multidrug resistant (MDR) variant MES-SA/Dx5 were conducted in order to investigate the role of heating rate in achieving a synergistic effect. The mode of cell death, induction of thermal tolerance and P-glycoprotein (P-gp) mediated MDR following two different rates of heating were studied.


METHODS
Doxorubicin (DOX) was used as the chemotherapy drug. A rapid rate hyperthermia was achieved by near infrared laser (NIR) excited indocyanine green (ICG) dye (absorption maximum at 808 nm, ideal for tissue penetration). A slow rate hyperthermia was provided by a cell culture incubator.


RESULTS
The potentiating effect of hyperthermia to chemotherapy can be maximised by increasing the rate of heating. When delivered at the same thermal dose, a rapid increase in temperature from 37°C to 43°C caused more cell membrane damage than gradually heating the cells from 37°C to 43°C and thus allowed for more intracellular accumulation of DOX. Meanwhile, the rapid rate laser-ICG hyperthermia at 43°C caused cell necrosis whereas the slow rate incubator hyperthermia at 43°C induced mild apoptosis. At 43°C a positive correlation between thermal tolerance and the length of hyperthermia exposure is identified.


CONCLUSIONS
This study shows that by increasing the rate of heating, less thermal dose is needed in order to overcome P-gp mediated MDR.
Department of Mechanical Engineering, Temple University, Philadelphia, Pennsylvania, USA.
Yuan
Y
Tang
Anthony J
AJ
McGoron
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D004317:Doxorubicin / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D009336:Necrosis; D014594:Uterine Neoplasms / Q000628:therapy*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018840:HSP70 Heat-Shock Proteins; D004317:Doxorubicin; D053148:Caspase 3