Regional chemotherapy in the treatment of advanced pancreatic cancer — is it relevant?

Lorenz, Matthias; Heinrich, Stefan; Staib-Sebler, E.; Köhne, Claus‐Henning; Wils, J.; Nordlinger, Bernard; Encke, A.

doi:10.1016/s0959-8049(00)00073-3

Cited by 29 publications

(15 citation statements)

References 20 publications

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“…2) are likely to yield a tumor that is resistant to a variety of conventional chemotherapies and to radiation (3,4). Interestingly, pancreatic tumors are sensitive to the restoration of p53 (5) but not to restoration of p16/RB1 or silencing of K-ras (6,7), which only result in suppression of growth without significant effect on apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma

Kokkinakis

Liu

Neuner

2005

Molecular Cancer Therapeutics

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Section: Introductionmentioning

confidence: 99%

Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma

Kokkinakis

Liu

Neuner

2005

Molecular Cancer Therapeutics

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“…Frequent genetic modifications in pancreatic carcinomas include activation of the K-ras oncogene (85-95%) and inactivation of the p16͞RB1 (Ͼ90%), p53 (75%), and DPC4 (55%) tumor suppressor genes (2,7,8). These findings highlight the complexity of this cancer and may provide a partial explanation for the aggressiveness and inherent resistance of this neoplasm to conventional therapies, including chemotherapy and radiation (3)(4)(5)(6).…”

mentioning

confidence: 95%

“…Moreover, long-term survival for patients with organ-confined disease is only 20%, and in the majority of cases, in which the disease when diagnosed has already spread past the pancreas, survival is only 4% (2)(3)(4)(5)(6). These findings underscore the need for developing improved therapies for this aggressive cancer.…”

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confidence: 99%

A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells

Lebedeva

Gopalkrishnan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

143

210

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Pancreatic cancer is an extremely aggressive neoplasm whose incidence equals its death rate. Despite intensive analysis, the genetic changes that mediate pancreatic cancer development and effective therapies for diminishing the morbidity associated with this disease remain unresolved. Through subtraction hybridization, we have identified a gene associated with induction of irreversible growth arrest, cancer reversion, and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). Ectopic expression of mda-7 when using a recombinant adenovirus, Ad.mda-7, results in growth suppression and apoptosis in a broad spectrum of human cancers with diverse genetic defects, without exerting deleterious effects in normal human epithelial or fibroblast cells. Despite the apparently ubiquitous antitumor effects of mda-7, pancreatic carcinoma cells are remarkably refractory to Ad.mda-7 induced growth suppression and apoptosis. In contrast, the combination of Ad.mda-7 with antisense phosphorothioate oligonucleotides, which target the K-ras oncogene (a gene that is mutated in 85 to 95% of pancreatic carcinomas), induces a dramatic suppression in growth and a decrease in cell viability by induction of apoptosis. In mutant K-ras pancreatic carcinoma cells, programmed cell death correlates with expression and an increase, respectively, in MDA-7 and BAX proteins and increases in the ratio of BAX to BCL-2 proteins. Moreover, transfection of mutant K-ras pancreatic carcinoma cells with an antisense K-ras expression vector and infection with Ad.mda-7 inhibits colony formation in vitro and tumorigenesis in vivo in nude mice. These intriguing observations demonstrate that a combinatorial approach, consisting of a cancer-specific apoptosis-inducing gene and an oncogene inactivation strategy, may provide the foundation for developing an effective therapy for pancreatic cancer.

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“…1). This stop-Xow perfusion technique is well suited for large body segments such as the thoracic and abdominal cavities in the pelvis and the limb [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

Kuemmerle

Décosterd

Buclin

et al. 2008

Cancer Chemother Pharmacol

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Purpose As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-Xow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n = 8, and cholangiocarcinoma of the liver, n = 1). Experimental design Gemcitabine at 500, 750 and 1,125 mg/m 2 was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-Xow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2Ј,2Ј-diXuorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20 min of stop-Xow perfusion, and in peripheral plasma for 420 min. Blood gases were monitored during the stop-Xow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH · 7.2, pO 2 nadir ratio ·0.70 or pCO 2 peak ratio ¸1.35. The tolerability of this procedure was also assessed. Results Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20 min of stop-Xow perfusion, with C max levels in the abdominal circuit of 246 ( §37%), 2,039 ( §77%) and 4,780 ( §7.3%) g/ml for the three dose levels 500, 750 and 1,125 mg/m 2 , respectively. These C max were between 13 ( §51%) and 290 ( §12%) times higher than those measured in the peripheral plasma. 123Similarly, the abdominal exposure to gemcitabine, calculated as AUC t0-20 , was between 5.5 ( §43%) and 200 ( §66%)-fold higher than the systemic exposure. Locoregional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P < 0.01 for C max and AUC t0-20 , both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to diVerentiate the respective contributions of systemic and regional exposures. A signiWcant correlation (P < 0.05) was found between systemic C max of gemcitabine and the nadir of both leucocytes and neutrophils. Conclusions Regional exposure to gemcitabine-the current standard drug for advanced adenocarcinoma of the pancreas-can be markedly enhanced using an optimised hypoxic stop-Xow perfusion technique, with acceptable toxicities up to a dose of 1,125 mg/m 2 . However, the activity of gemcitabine under hypoxic conditions is not as Wrmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted Wrst to evaluate the tolerance in a phase I study and later on to assess whether it does impr...

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Regional chemotherapy in the treatment of advanced pancreatic cancer — is it relevant?

Cited by 29 publications

References 20 publications

Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma

Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma

A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells

A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

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