Enhancement of cytotoxicity of doxorubicin by verapamil in the hepatic artery infusion for liver tumors in rats

Miyazaki, Masaru; Shimoda, Tsukasa; Itoh, Hiroshi; Koyama, Takashi; Iinuma, Katsuhiro; Koyama, Takashi; Nakagawa, Kohji; Andoh, Katsuhiko; Anbiru, Satoru; Ohtawa, Satoshi; Ogata, Atsushi; Yasuda, Norio; Hayashi, S.; Nakajima, Nobuyuki

doi:10.1002/1097-0142(19930715)72:2<349::aid-cncr2820720207>3.0.co;2-o

Cited by 7 publications

(2 citation statements)

References 12 publications

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“…In the study of hepatoma, TACE could enhance the expression of VEGF [18][19][20][21] , but not the MVD level [22] or expression of b-FGF [19,22] . All these studies were retrospective.…”

Section: Introductionmentioning

confidence: 99%

Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: An experimental study

Li¹,

Feng²,

Zheng³

et al. 2003

WJG

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AIM:After transarterial chemoembolization (TACE), the residual cancer cells are under extensive hypoxic or even anoxic environment. Hypoxia can lead to adaptive responses. For example, angiogenesis will help these cells survive. In this study, we examined the effect of TACE on angiogenesis and expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) and to assess their relevance to Walker-256 transplanted hepatoma. METHODS:Male Wistar rats were inoculated with Walker-256 tumor in the left lobe of liver. Angiography and transarterial chemoembolization were performed at d14 after transplantation. Sixty rats bearing walker-256 transplanted hepatoma were randomly divided into control group, arterial infusion group and TACE group. Each group consisted of twenty rats. Normal saline, 5-Fu, 5-Fu and lipiodol were infused through hepatic artery respectively. Two weeks after the infusion, staining of factor VIII, VEGF and b-FGF was performed by immunohistochemistry method in routine paraffin-embeded sections. Microvessel density (MVD) was counted in endothelial cells with positive factor VIII. Their expression levels were analyzed in conjunction with the pathologic features. RESULTS:While a smaller tumor volume was found in TACE group (F=37.818, P<0.001), no statistical differences between MVD and expression of VEGF and b-FGF were found among the 3 groups. MVD of the control group, chemotherapy group and chemoemoblization group was 80.84±24. 24, 83.05±20.29 and 85.20±23.91 (F=0.193, P=0.873

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“…In the study of hepatoma, TACE could enhance the expression of VEGF [18][19][20][21] , but not the MVD level [22] or expression of b-FGF [19,22] . All these studies were retrospective.…”

Section: Introductionmentioning

confidence: 99%

Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: An experimental study

Li¹,

Feng²,

Zheng³

et al. 2003

WJG

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“…Repetitive locoregional administration of drugs can be achieved by regional infusions via the hepatic artery (Riemenschneider et al, 1988;Miyazaki et al, 1993;Kemeny et al, 1994). Thus repeated delivery of adenoviral vectors via the hepatic artery may further increase the efficacy of transfection.…”

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confidence: 99%

Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

et al. 2002

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Ras mutations are present in 40 -50% of colorectal cancers. Inactivating this oncogene may therefore reduce proliferation capacity. In order to target ras we studied the transduction efficacy and anti tumour activity of an adenoviral vector expressing an intracellular, neutralizing single chain antibody to p21-ras (Y28). In in vitro studies transfection levels of the K-ras mutated rat colon carcinoma cell line CC531 were studied using the LacZ marker gene. In our in vivo liver metastases model different routes of administration were evaluated to determine which regimen resulted in the best transfection levels and tumour responses: intravenous injection, intratumoural injection, isolated liver perfusion, or hepatic artery infusion. CC531 cells are readily transfected in vitro, resulting in significant inhibition of tumour cell proliferation by the Y28 construct. Intravenous injection did not result in any measurable transfection. Intratumoural injection resulted only in the transfection of tumour cells along the needle track. IHP as well as single HAI achieved low transfection levels of tumour tissue. Expression of Y28 was demonstrated in tumours after IT injection, HAI and IHP. Whereas, repeated HAI's clearly achieved expression in and around tumour associated vessels. Only five times repeated HAI's with Y28 resulted in a tumour response: in all animals tumour growth was inhibited, and in three rats out of eight a complete regression of the liver tumours was observed.

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Verapamil-reversing concentrations induce blood flow changes that could counteract in vivo the MDR-1-modulating effects

Ramirez

Munck

Zhang

et al. 1994

Cancer

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Background. Intraarterial hepatic (IAH) administration of verapamil should achieve mdr‐1‐reversing concentrations with reduced cardiac toxicity. The authors have explored the tolerance of its IAH administration and its effects on doxorubicin pharmacodynamics. Methods. Verapamil was given to rabbits by intravenous or IAH administration, and its effects on heart rates were compared. Doxorubicin then was given intravenously either with IAH verapamil or with an IAH control perfusion, and tumor and liver drug concentrations were determined. Hepatic blood flow changes were studied by the administration of 99mTc‐albumin macroaggregates(99mTc‐MAA) under verapamil IAH perfusions. Results. Compared with the intravenous route, IAH administration of verapamil was not toxic, and cardiac effects were reduced significantly. Its effect on doxorubicin distribution was detrimental, because the tumor‐liver doxorubicin concentration ratios were lower in the verapamil group (0.23 vs. 3.37; P < 0.05). Tumor doxorubicin concentrations were lower when verapamil was coinfused [43 vs. 573 ng/100 mg tissue; P < 0.05]. In normal liver tissue, increased amounts of doxorubicin and metabolites were observed. The verapamil IAH perfusions with 99mTc‐MAA confirmed a differential action on tumor and normal vessels; the distribution of radionuclide was diverted away from the tumor bed significantly when verapamil was administered (tumor‐to‐liver ratio of 25.3 control rabbits vs. 5.99 rabbits who received verapamil; P < 0.05). Conclusions. Reversing the concentrations of verapamil provoked changes in the distribution of the liver blood flow. The hemodynamic effects of verapamil regional perfusions could counteract in vivo its potential mdr‐1‐reversing properties.

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Enhancement of cytotoxicity of doxorubicin by verapamil in the hepatic artery infusion for liver tumors in rats

Cited by 7 publications

References 12 publications

Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: An experimental study

Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: An experimental study

Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

Verapamil-reversing concentrations induce blood flow changes that could counteract in vivo the MDR-1-modulating effects

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