Flow Cytometric Bromodeoxyuridine/DNA Analysis of Hyperthermia and/or Adriamycin for Human Pancreatic Adenocarcinoma Cell Line Capan‐2

Nakata, Bunzo; Chung, Yong‐Suk; Yokomatsu, Hideaki; Sawada, Tetsuji; Kubo, Toshiaki; Kondo, Yasuyuki; Satake, Katsusuke; Sowa, Michio

doi:10.1111/j.1349-7006.1992.tb01952.x

Cited by 8 publications

(3 citation statements)

References 9 publications

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“…In most ex periments, experimental cell lines and experi mental animal tumors have been used. Hu man tumors were used for experiments in small numbers [31,32] Our previously performed trial showed no effect of42°C hyperthermia in enhancing the growth-inhibitory effect of 5-FU on human gastric adenocarcinoma cells [unpublished data]. The present study has confirmed our previously obtained data and supports the conclusion that 42 °C hyperthermia does not enhance the growth-inhibitory effects of 5-FU on human epithelial tumor cell lines.…”

Section: Discussionsupporting

confidence: 82%

In vitro Effect of 5-Fluorouracil, Verapamil and Hyperthermia on the Human Pancreatic Adenocarcinoma Cell Line ASPC-1

et al. 1994

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The purpose of this study was to assess the efficacy of verapamil (20 μM) and hyperthermia (42 °C) as modifiers of 5-fluorouracil (5-FU) used at different concentrations, in inhibiting the growth of human pancreatic adenocarcinoma cells. Combined verapamil and hyperthermia treatment significantly decreased cell count by 63.8% when compared to the control. Verapamil drastically enhanced the growth inhibitory effect of 5-FU at all concentrations. At high-concentration 5-FU (50 μg/ml), verapamil and hyperthermia had a synergistic growth-inhibitory effect and caused a significant decrease in cell count by 81.4% in comparison to the control. The modalities analyzed in this study require further investigation and have potential for clinical applicability to pancreatic cancer therapy in the future.

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Section: Discussionsupporting

confidence: 82%

In vitro Effect of 5-Fluorouracil, Verapamil and Hyperthermia on the Human Pancreatic Adenocarcinoma Cell Line ASPC-1

et al. 1994

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“…Some studies [ 18, 19] have reported flow cytometric analysis of chemohyperthermia in the cell cycle of cultured cells in vitro , reporting increases in the accumulation of the G2/M phase and/or late S phase after combined therapy with hyperthermia (41°C) and low concentrations of adriamycin (0.1 or 0.5 μg/mL). Conversely, DNA distribution histograms showed no accumulation of cells with late S and G2 DNA content in cells exposed to higher concentrations of adriamycin (0.5–10 μg/mL) [ 19].…”

Section: Discussionmentioning

confidence: 99%

Heat‐induced membrane damage combined with adriamycin on prostate carcinoma PC‐3 cells: correlation of cytotoxicity, permeability and P‐glycoprotein or metallothionein expression

Moriyama‐Gonda

Igawa

Shiina

et al. 1998

British Journal of Urology

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Objective To assess heat‐induced membrane damage in a prostate cancer cell line when combined with adriamycin treatment. Materials and methods The changes in intracellular adriamycin accumulation, cell proliferation and cell‐cycle fractions were examined after human prostate carcinoma PC‐3 cells were exposed to heat and/or further treatment with adriamycin. Proliferation and the cell cycle were determined using adherent cell analysis and sorting laser cytometry (ACAS) or flow cytometry. P‐glycoprotein (PGP) and metallothionein (MT) expression, which may have a physiological role in the transport of or reduction in cytotoxicity of some anticancer drugs, were also analysed after cells were exposed to heat, using immunohistochemical or flow cytometric methods. Results There was a significant increase in intracellular adriamycin accumulation, related to both influx (P<0.05) and efflux (P<0.01), in cells treated with adriamycin, especially after heating them at 44°C for 1 h. There was a significant decrease in cell proliferation of preheated cells when exposed to adriamycin, especially at 44°C (P<0.05). In the cell‐cycle analysis, cells preheated at 44°C showed partial accumulation in the debris or apoptotic fraction at 24 h, and many cells accumulated in these fractions at 48 h. There was significantly less PGP or MT expression in cells preheated at 44°C than in control cells or cells preheated at 41°C (P<0.01). This reduction in PGP or MT level by heating may inhibit drug efflux and thus increase intracellular drug level at elevated temperatures. Conclusions These results suggest that hyperthermia may damage the drug‐exclusion mechanism in these cells and thus increase the effectiveness of drug action.

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“…In fact, we saw a linear increase in β-glucuronidase activity between 37°C and 57°C (data not shown). Thus, hyperthermia could augment drug targeting by elevated β-glucuronidase activity and additionally increase drug accumulation and cytotoxicity in tumor cells (Nakata et al 1992;Asaumi et al 1995), possibly leading to a potentiation of cytostatic effects.…”

Section: Discussionmentioning

confidence: 97%

Expression and function of β-glucuronidase in pancreatic cancer: potential role in drug targeting

Sperker

Werner

Mürdter

et al. 2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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Improvement of non-surgical strategies is a pivotal task in the treatment of pancreatic cancer. Response to treatment with most anticancer agents has been very poor, probably due to insufficient drug concentration in tumor tissue. Increased response rates during chemotherapy might be achieved by dose escalation; however, this approach is often hampered by severe side effects. One strategy to overcome these adverse effects is application of nontoxic glucuronide prodrugs from which the active moiety is released by beta-glucuronidase within or near the tumor. The use of glucuronide prodrugs in pancreatic cancer requires increased expression of the enzyme in the diseased tissue, a problem that has not been addressed so far. We therefore investigated function and expression of beta-glucuronidase in tissue samples from human healthy pancreas (n=7) and pancreatic adenocarcinoma (n=8), respectively. Comparing the ability of tissue homogenates to cleave the standard substrate 4-methylumbelliferyl-beta-D-glucuronide, we found a significantly increased specific beta-glucuronidase activity (P<0.05) in pancreatic cancer (median: 133; 75% percentile: 286; 25% percentile: 111 nmol/mg per h) as compared to healthy pancreas (median: 74; 75% percentile: 113; 25% percentile: 71 nmol/mg per h). Enzyme kinetic experiments with the model prodrug N-[4-beta-glucuronyl-3-nitrobenzyloxycarbonyl] doxorubicin (HMR 1826) demonstrated bioactivation of HMR 1826 by pancreatic beta-glucuronidase. Enzymatic activity was found to be closely related to enzyme contents (r=0.87) as assessed by Western blot analysis. Our data indicate that increased beta-glucuronidase activity in pancreatic cancer seems to be due to an elevated steady-state level of the protein. This may be the basis for new therapeutic strategies in treatment of pancreatic carcinoma by using glucuronide prodrugs of anticancer agents.

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Flow Cytometric Bromodeoxyuridine/DNA Analysis of Hyperthermia and/or Adriamycin for Human Pancreatic Adenocarcinoma Cell Line Capan‐2

Cited by 8 publications

References 9 publications

In vitro Effect of 5-Fluorouracil, Verapamil and Hyperthermia on the Human Pancreatic Adenocarcinoma Cell Line ASPC-1

In vitro Effect of 5-Fluorouracil, Verapamil and Hyperthermia on the Human Pancreatic Adenocarcinoma Cell Line ASPC-1

Heat‐induced membrane damage combined with adriamycin on prostate carcinoma PC‐3 cells: correlation of cytotoxicity, permeability and P‐glycoprotein or metallothionein expression

Expression and function of β-glucuronidase in pancreatic cancer: potential role in drug targeting

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