Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma.

Kemeny, Nancy E.; Conti, John A.; Cohen, A.; Campana, P.; Huang, Ying; Shi, Wei Ji; Botet, José; Pulliam, Stephanie R.; Bertino, Joseph R.

doi:10.1200/jco.1994.12.11.2288

Cited by 156 publications

(61 citation statements)

References 8 publications

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“…Consistent with the data from treated patients (12,13), HA dexamethasone specifically protects the biliary epithelium in treated dogs as shown in Tables 2 and 3. Dexamethasone produced a marked decrease in portal fibrosis and bile duct injury ( Table 2).…”

Section: Discussionsupporting

confidence: 79%

“…Subsequently, the Sloan-Kettering group added dexamethasone in an attempt to ameliorate pericholangitis and, thereby, to decrease biliary toxicity, allowing for more HA FdUrd/leucovorin to be administered (12,13). When dexamethasone was coadministered, biliary toxicity was diminished, more intense chemotherapy was tolerated, and the response rate improved.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Dexamethasone or Celecoxib on Biliary Toxicity after Hepatic Arterial Infusion of 5-Fluorodeoxyuridine in a Canine Model

Ensminger¹,

Knol²,

DeRemer³

et al. 2004

Cancer Research

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Previous work has shown that in humans the dose-limiting toxicity for fluorodeoxyuridine [2-fluoro-5-deoxyuridine (FdUrd)] when administered by hepatic arterial infusion is biliary sclerosis. The current study was undertaken to attempt to modify this toxicity in a canine model that has been demonstrated to closely mimic the clinical situation. Unlike previous studies using this model, in which animals were sacrificed after extensive fibrosis had already occurred, the current experiments were designed so that observations of pathology were made at an earlier time, when the initial inflammatory injury underlying the fibrotic process was still taking place. Implantable pumps were used to deliver FdUrd into the hepatic artery of animals at a rate of 0.3 mg/kg/day in the presence or absence of 10 mg/week dexamethasone or 100 mg/day of celecoxib for 35 days, at which time the animals were beginning to show signs of toxicity. After evaluation for radiological evidence of biliary obstruction, the animals were sacrificed and portions of their livers were processed for examination of microscopic pathology and 2-bromo-5deoxyuridine labeling index. Dexamethasone treatment protected the animals from biliary sclerosis determined radiologically, further validating this model as being representative of the response in humans. Similarly the Cox-2 inhibitor, celecoxib, appeared to provide protection against radiological changes of biliary stricture, although possibly to a lesser degree than the resultant from dexamethasone. In addition, FdUrd treatment caused elevation of the DNA 2-bromo-5deoxyuridine labeling index above control levels in biliary epithelial cells. Dexamethasone and celecoxib each significantly attenuated the FdUrd-induced elevation of DNA labeling index in biliary epithelium. These findings demonstrate the usefulness of this canine model for studying the mechanisms of drug-induced biliary sclerosis and reinforce the hypothesis that blocking inflammation may retard the progression of injury that eventually leads to fibrosis. This study suggests that clinical testing of celecoxib as a preventive for hepatic arterial-FdUrd induced biliary damage could prove valuable.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Effects of Dexamethasone or Celecoxib on Biliary Toxicity after Hepatic Arterial Infusion of 5-Fluorodeoxyuridine in a Canine Model

Ensminger¹,

Knol²,

DeRemer³

et al. 2004

Cancer Research

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“…In fact, Dex in combination with chemotherapeutic drugs has been trialed in the clinic through hepatic arterial infusion. The results show reduced toxicity while maintaining an excellent response rate and survival 45,46 . In these multidrug clinical trials, Dex possibly enhances the resistance of tumour cells to one or two drugs, but increases the sensitivity of tumour cells to other drugs.…”

Section: Discussionmentioning

confidence: 75%

Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

et al. 2013

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Gluconeogenesis is a fundamental feature of hepatocytes. Whether this gluconeogenic activity is also present in malignant hepatocytes remains unexplored. A better understanding of this biological process may lead to novel therapeutic strategies. Here we show that gluconeogenesis is not present in mouse or human malignant hepatocytes. We find that two critical enzymes 11b-HSD1 and 11b-HSD2 that regulate glucocorticoid activities are expressed inversely in malignant hepatocytes, resulting in the inactivation of endogenous glucocorticoids and the loss of gluconeogenesis. In patients' hepatocarcinoma, the expression of 11b-HSD1 and 11b-HSD2 is closely linked to prognosis and survival. Dexamethasone, an active form of synthesized glucocorticoids, is capable of restoring gluconeogenesis in malignant cells by bypassing the abnormal regulation of 11b-HSD enzymes, leading to therapeutic efficacy against hepatocarcinoma. These findings clarify the molecular basis of malignant hepatocyte loss of gluconeogenesis and suggest new therapeutic strategies.

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“…The activity of 5-fluorodeoxyuridine (5-FdUrd) is comparable to that of 5-Fluorouracil (5-FU) and due to extensive hepatic extraction, 5-FdUrd has a marked pharmacological advantage when administered via the hepatic artery (14,15). 5-FU is a pyrimidine analogue with the capacity to inhibit the biosynthesis of pyrimidine nucleotides.…”

Section: Discussionmentioning

confidence: 99%

Avemar, a nontoxic fermented wheat germ extract, attenuates the growth of sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells through induction of apoptosis

Szekeres¹

2009

Oncol Rep

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Abstract. Avemar (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. After 48 and 72 h of incubation, Avemar inhibited the growth of sensitive H9 cells with IC 50 values of 290 and 200 μg/ml, whereas the growth of 5-FdUrd/Ara-C cross-resistant H9 cells was attenuated with IC 50 values of 180 and 145 μg/ml, respectively. Treatment with 300 μg/ml MSC for 48 h caused dosedependent induction of apoptosis in 48% of sensitive H9 cells. In cross-resistant H9 cells, incubation with 200 μg/ml Avemar for 48 h led to 41% of apoptotic tumor cells. Growth arrest of sensitive H9 cells after exposure to various concentrations of MSC occurred mainly in the S phase of the cell cycle, thereby increasing the cell population from 54 to 73% while depleting cells in the G0-G1 phase from 40 to 19%. Growth arrest in cross-resistant H9 cells occurred also mainly in the S phase, increasing the cell population from 45 to 68% while depleting cells in the G0-G1 phase from 45 to 31%. As MSC treatment likely overcomes 5-FdUrd/Ara-C resistance, further investigations to elucidate the exact mechanisms are warranted. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.

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Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma.

Abstract: The addition of Dec to hepatic arterial FUDR and LV reduces biliary toxicity while maintaining an excellent response rate and survival. We recommend that this treatment be studied further.

Cited by 156 publications

References 8 publications

Effects of Dexamethasone or Celecoxib on Biliary Toxicity after Hepatic Arterial Infusion of 5-Fluorodeoxyuridine in a Canine Model

Effects of Dexamethasone or Celecoxib on Biliary Toxicity after Hepatic Arterial Infusion of 5-Fluorodeoxyuridine in a Canine Model

Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

Avemar, a nontoxic fermented wheat germ extract, attenuates the growth of sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells through induction of apoptosis

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