There is little information on the pharmacokinetics and pharmacodynamics of doxorubicin (DXR) administered during locoregional treatments of colon carcinoma under hyperthermic conditions. The aim of this study was to evaluate distribution and activity of DXR in healthy tissue and tumor tissues under hyperthermic conditions by using an experimental model of ex vivo isolated vascular perfusion of human colon segments bearing primary carcinoma. The influence of topoisomerase-IIalpha (TPI2alpha) expression on the anti-cancer activity of DXR combined with heat was evaluated as well. Twenty seven colon segments surgically resected for primary carcinoma were perfused ex vivo under physiological conditions (group A, n = 7), with DXR (group B, n = 6), under hyperthermic conditions (group C, n = 6), and with the combination DXR-hyperthermia (group D, n = 8). Samples of perfusate and tissues (normal and pathologic) were collected during 90 minutes of perfusion. Doxorubicin concentration in perfusate and tissues was assessed with high-performance liquid chromatography. Protein expression of TPI2alpha, the main molecular target of DXR, was measured by image analysis in normal mucosa and tumor samples. Drug uptake was increased by heat equally in healthy and diseased tissue. Under hyperthermic conditions, DXR activity was significantly higher in pathologic mucosa than in normal mucosa. Furthermore, the activity of DXR combined with heat correlated with baseline TPI2alpha levels in tumor tissue. From these findings, it appears that heat sensitizes tumor cells-but not normal mucosa-to DXR activity. Furthermore, protein levels of TPI2alpha in pretreatment samples could predict tumor sensitivity to DXR.
Doxorubicin activity is enhanced by hyperthermia in a model of ex vivo vascular perfusion of human colon carcinoma / Pilati, Pierluigi; Mocellin, Simone; Rossi, CARLO RICCARDO; Scalerta, ROMANO GABRIELE; Alaggio, Rita; Giacomelli, L; Geroni, C; Nitti, Donato; Lise, M.. - In: WORLD JOURNAL OF SURGERY. - ISSN 0364-2313. - 27:6(2003), pp. 640-646. [10.1007/s00268-003-6804-3]
Doxorubicin activity is enhanced by hyperthermia in a model of ex vivo vascular perfusion of human colon carcinoma
ALAGGIO, RITA;
2003
Abstract
There is little information on the pharmacokinetics and pharmacodynamics of doxorubicin (DXR) administered during locoregional treatments of colon carcinoma under hyperthermic conditions. The aim of this study was to evaluate distribution and activity of DXR in healthy tissue and tumor tissues under hyperthermic conditions by using an experimental model of ex vivo isolated vascular perfusion of human colon segments bearing primary carcinoma. The influence of topoisomerase-IIalpha (TPI2alpha) expression on the anti-cancer activity of DXR combined with heat was evaluated as well. Twenty seven colon segments surgically resected for primary carcinoma were perfused ex vivo under physiological conditions (group A, n = 7), with DXR (group B, n = 6), under hyperthermic conditions (group C, n = 6), and with the combination DXR-hyperthermia (group D, n = 8). Samples of perfusate and tissues (normal and pathologic) were collected during 90 minutes of perfusion. Doxorubicin concentration in perfusate and tissues was assessed with high-performance liquid chromatography. Protein expression of TPI2alpha, the main molecular target of DXR, was measured by image analysis in normal mucosa and tumor samples. Drug uptake was increased by heat equally in healthy and diseased tissue. Under hyperthermic conditions, DXR activity was significantly higher in pathologic mucosa than in normal mucosa. Furthermore, the activity of DXR combined with heat correlated with baseline TPI2alpha levels in tumor tissue. From these findings, it appears that heat sensitizes tumor cells-but not normal mucosa-to DXR activity. Furthermore, protein levels of TPI2alpha in pretreatment samples could predict tumor sensitivity to DXR.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
