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1.
Adv Drug Deliv Rev ; 163-164: 145-156, 2020.
Article in English | MEDLINE | ID: mdl-32247801

ABSTRACT

Hyperthermia, i.e. heating the tumor to a temperature of 40-43 °C is considered by many a valuable treatment to sensitize tumor cells to radiotherapy and chemotherapy. In recent randomized trials the great potential of adding hyperthermia to chemotherapy was demonstrated for treatment of high risk soft tissue sarcoma: +11.4% 5 yrs. overall survival (OS) and for ovarian cancer with peritoneal involvement nearly +12 months OS gain. As a result interest in combining chemotherapy with hyperthermia, i.e. thermochemotherapy, is growing. Extensive biological research has revealed that hyperthermia causes multiple effects, from direct cell kill to improved oxygenation, whereby each effect has a specific temperature range. Thermal sensitization of the tumor cell for chemotherapy occurs for many drugs at temperatures ranging from 40 to 42 °C with little additional increase of sensitization at higher temperatures. Increasing perfusion/oxygenation and increased extravasation are two other important hyperthermia induced mechanisms. The combination of free drug and hyperthermia has not been found to increase tumor drug concentration. Hence, enhanced effectiveness of free drug will depend on the thermal sensitization of the tumor cells for the applied drug. In contrast to free drugs, experimental animal studies combining hyperthermia and thermo-sensitive liposomal (TSL) drugs delivery have demonstrated to result in a substantial increase of the drug concentration in the tumor. For TSL based chemotherapy, hyperthermia is critical to both increase perfusion and extravasation as well as to trigger TSL drug release, whereby the temperature controlled induction of a local high drug concentration in a highly permeable vessel is driving the enhanced drug uptake in the tumor. Increased drug concentrations up to 26 times have been reported in rodents. Good control of the tissue temperature is required to keep temperatures below 43 °C to prevent vascular stasis. Further, careful timing of the drug application relative to the start of heating is required to benefit optimal from the combined treatment. From the available experimental data it follows that irrespective whether chemotherapy is applied as free drug or using a thermal sensitive liposomal carrier, the optimal thermal dose for thermochemotherapy should be 40-42 °C for 30-60 min, i.e. equivalent to a CEM43 of 1-15 min. Timing is critical: most free drug should be applied simultaneous with heating, whereas TSL drugs should be applied 20-30 min after the start of hyperthermia.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems/methods , Hyperthermia, Induced/methods , Liposomes/chemistry , Neoplasms/drug therapy , Antineoplastic Agents/pharmacokinetics , Drug Liberation , Humans , Hyperthermia/metabolism , Temperature , Tumor Microenvironment/physiology
2.
Adv Drug Deliv Rev ; 163-164: 125-144, 2020.
Article in English | MEDLINE | ID: mdl-32092379

ABSTRACT

Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems/methods , Hyperthermia, Induced/methods , Neoplasms/drug therapy , Antineoplastic Agents/pharmacokinetics , Humans , Hyperthermia, Induced/instrumentation , Nanoparticles/chemistry , Neoplasms/blood supply , Neoplasms/physiopathology , Temperature , Thermometry , Time Factors , Tumor Microenvironment/physiology
3.
Oncogene ; 34(39): 5055-68, 2015 Sep 24.
Article in English | MEDLINE | ID: mdl-25531314

ABSTRACT

Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development.


Subject(s)
Carcinogenesis , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Smad4 Protein/physiology , Animals , Cell Line, Tumor , Gene Knockdown Techniques , Gene Silencing , Humans , Mice , Phosphorylation , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Smad4 Protein/genetics
4.
Contrast Media Mol Imaging ; 8(4): 340-9, 2013.
Article in English | MEDLINE | ID: mdl-23613437

ABSTRACT

Experimental evidence supports an association between heterogeneity in tumor perfusion and response to chemotherapy/radiotherapy, disease progression and malignancy. Therefore, changes in tumor perfusion may be used to assess early effects of tumor treatment. However, evaluating changes in tumor perfusion during treatment is complicated by extensive changes in tumor type, size, shape and appearance. Therefore, this study assesses the regional heterogeneity of tumors by dynamic contrast-enhanced MRI (DCE-MRI) and evaluates changes in response to isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan. Data were acquired in an experimental cancer model, using a macromolecular contrast medium, albumin-(Gd-DTPA)45. Small fragments of BN 175 (a soft-tissue sarcoma) were implanted in eight brown Norway rats. MRI of five drug-treated and three sham-treated rats was performed at baseline and 1 h after ILP intervention. Properly co-registered baseline and follow-up DCE-MRI were used to estimate the volume transfer constant (K(trans) ) pharmacokinetic maps. The regional heterogeneity was estimated in 16 tumor sectors and presented in cumulative map-volume histograms. On average, ILP-treated tumors showed a decrease in regional heterogeneity on the histograms. This study shows that heterogenic changes in regional tumor perfusion, estimated using DCE-MRI pharmacokinetic maps, can be measured and used to assess the short-term effects of a potentially curative treatment on the tumor microvasculature in an experimental soft-tissue sarcoma model.


Subject(s)
Chemotherapy, Cancer, Regional Perfusion/methods , Extremities/pathology , Magnetic Resonance Imaging/methods , Sarcoma/diagnosis , Animals , Contrast Media , Male , Rats
5.
Br J Cancer ; 107(7): 1153-8, 2012 Sep 25.
Article in English | MEDLINE | ID: mdl-22929879

ABSTRACT

BACKGROUND: Although widely fragmented BMs have been associated with adverse outcome in several cancer types, comparatively little is known with respect to its effect on the prognosis of pancreatic cancer. The aim of the current study was therefore to determine the prognostic value of tumour basement membrane (BM) continuity in two anatomically closely related, however, prognostically different tumours, pancreatic head- and periampullary cancer. METHODS: Tumour BM continuity was determined by immunohistochemical staining of its two major components, laminin and collagen type IV. Associations were made with recurrence free survival (RFS), cancer-specific survival (CSS), overall survival (OS) and conventional prognostic factors. RESULTS: Fifty-nine and 61% of pancreatic head and periampullary tumours, respectively, showed limited BM laminin expression. Whereas 43% and 41% of pancreatic head and periampullary cancers, respectively, showed limited BM collagen type IV expression. Limited BM laminin was associated with poor outcome following curative resection of pancreatic head cancer (P=0.034, 0.013 and 0.017 for RFS, CSS and OS, respectively). Two and a half times as many patients with ≥ 25% BM laminin were recurrence free and alive 5 years following resection compared with those with limited BM laminin. Although staining patterns of both BM components were weakly correlated with each other, BM collagen type IV expression was not significantly associated with outcome in either tumour type. CONCLUSION: Discontinuous BMs, determined by laminin expression, are associated with poor outcome following curative resection of pancreatic head cancer.


Subject(s)
Basement Membrane/metabolism , Basement Membrane/pathology , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Laminin/biosynthesis , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Collagen Type IV/metabolism , Disease-Free Survival , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Randomized Controlled Trials as Topic , Retrospective Studies
6.
Eur J Surg Oncol ; 38(11): 1058-64, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22633450

ABSTRACT

BACKGROUND: Pancreatic cancer has a dismal prognosis. Attempts have been made to improve outcome by several 5-FU based adjuvant treatment regimens. However, the results are conflicting. There seems to be a continental divide with respect to the use of 5-FU based chemoradiotherapy (CRT). Furthermore, evidence has been presented showing a different response of pancreatic head and periampullary cancer to 5-FU based CRT. Expression of thymidylate synthase (TS) has been associated with improved outcome following 5-FU based adjuvant treatment in gastrointestinal cancer. This prompted us to determine the differential expression and prognostic value of TS in pancreatic head and periampullary cancer. PATIENTS AND METHODS: TS protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 212 patients following microscopic radical resection (R0) of pancreatic head (n = 98) or periampullary cancer (n = 114). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS), and conventional prognostic factors. RESULTS: High cytosolic TS expression was present in 26% of pancreatic head tumours and 37% of periampullary tumours (p = .11). Furthermore, TS was an independent factor predicting favourable outcome following curative resection of pancreatic head cancer (p = .003, .001 and .001 for RFS, CSS and OS, respectively). In contrast, in periampullary cancer, TS was not associated with outcome (all p > .10). CONCLUSION: TS, was found to be poorly expressed in both pancreatic head and periampullary cancer and identified as an independent prognostic factor following curative resection of pancreatic head cancer.


Subject(s)
Adenocarcinoma/enzymology , Ampulla of Vater , Common Bile Duct Neoplasms/enzymology , Pancreatic Neoplasms/enzymology , Thymidylate Synthase/analysis , Adenocarcinoma/therapy , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/therapeutic use , Biomarkers, Tumor/analysis , Chemoradiotherapy , Common Bile Duct Neoplasms/therapy , Female , Fluorouracil/therapeutic use , Humans , Male , Middle Aged , Pancreatic Neoplasms/therapy , Prognosis
8.
Br J Cancer ; 95(12): 1663-9, 2006 Dec 18.
Article in English | MEDLINE | ID: mdl-17106443

ABSTRACT

Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents.


Subject(s)
Chemotherapy, Cancer, Regional Perfusion , Drug Delivery Systems , Histamine/therapeutic use , Sarcoma/drug therapy , Animals , Antibiotics, Antineoplastic/pharmacology , Cardiovascular Agents/pharmacology , Cells, Cultured , Doxorubicin/pharmacology , Drug Synergism , Drug Therapy, Combination , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Hindlimb , Humans , Male , Rats , Rats, Inbred BN , Sarcoma/blood supply , Umbilical Veins/cytology , Umbilical Veins/drug effects
9.
Cell Biochem Biophys ; 44(1): 157-69, 2006.
Article in English | MEDLINE | ID: mdl-16456244

ABSTRACT

Tumor response is strongly enhanced by addition of tumor necrosis factor (TNF)-alpha to chemotherapy in local-regional perfusion. TNF primarily targets the endothelial lining of the tumor-associated vasculature, thereby improving permeability of the vascular bed. This augments uptake of the coadministered chemotherapeutic drug in the tumor. In vitro, however the high dose of TNF did not directly affect endothelial cells, indicating that other factors, most likely TNF-induced, are involved in the antivascular activities observed in vivo. This is supported by in vivo studies in our laboratory in which depletion of leukocytes resulted in loss of the antivascular activity of TNF. The present study examined the role of peripheral blood mononuclear cells (PBMCs) on endothelial cells by exposing them to TNF, interferon (IFN)-gamma, and PBMCs. We observed morphological changes of the endothelial cells when exposed to TNF in combination with IFN. Endothelial cells became elongated. and gaps between the cells formed. Addition of PBMCs enhanced these alterations. The endothelial layer became disrupted with highly irregular-shaped cells displaying large gap formations. PBMCs also contributed to an increased permeability of the endothelial layer without augmenting apoptosis. Replacing PBMC by interleukin (IL)-1beta produced similar effect with regard to inhibition of cell growth, morphological changes, and induction of apoptosis. Blocking IL-1beta with a neutralizing antibody diminished the effects inflicted of PBMCs. These observations indicate that endogenously produced IL-1beta by primed PBMCs plays an important role in the antivascular effect of TNF.


Subject(s)
Cell Membrane Permeability/drug effects , Cytokines/pharmacology , Endothelial Cells/drug effects , Apoptosis/drug effects , Capillary Permeability/drug effects , Cell Shape/drug effects , Cells, Cultured , Coculture Techniques , Cytokines/physiology , Cytoskeleton/drug effects , Doxorubicin/pharmacology , Endothelial Cells/cytology , Endothelial Cells/metabolism , Humans , Interferon-gamma/pharmacology , Interleukin-1/pharmacology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Melphalan/pharmacology , Models, Biological , Neoplasms/blood supply , Neoplasms/metabolism , Tumor Necrosis Factor-alpha/pharmacology
10.
Eur J Surg Oncol ; 31(8): 897-904, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16084053

ABSTRACT

AIMS: To investigate the feasibility of hypoxic pelvic perfusion (HPP), using balloon catheter techniques as treatment modality for locally advanced pelvic malignancies. METHODS: In a phase I--II study, 16 patients with various non-resectable pelvic tumours were treated with two HPP with MMC and melphalan, followed by radiotherapy (25 Gy) and surgical resection if feasible. Toxicity and procedure related complications were documented. Tumour responses were assessed by MRI or CT. Pain reductive effects were assessed by evaluation of pain registration forms. RESULTS: HPP resulted in augmented regional drug concentrations with relatively low systemic levels. Some severe systemic toxicity was observed. One procedure related death occurred. Pain reduction effects were short-lived. Ten patients had radiological NC, two PD and one PR. In 11 patients surgical resection was performed, which was microscopically radical in six cases. Mean survival was 26.8 months (range 1--86). CONCLUSION: The seemingly favorable pharmacokinetic profiles observed with HPP in this and other studies can still lead to severe systemic toxicity. In terms of survival, local (re-)recurrence and pain reduction there seems no benefit of addition of HPP to pre-operative radiotherapy. HPP with MMC and melphalan, does not seem a therapeutic option in patients with locally advanced pelvic tumours.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents, Alkylating/therapeutic use , Catheterization/methods , Chemotherapy, Cancer, Regional Perfusion/methods , Melphalan/therapeutic use , Mitomycin/therapeutic use , Pelvic Neoplasms/drug therapy , Adult , Aged , Antibiotics, Antineoplastic/adverse effects , Antineoplastic Agents, Alkylating/adverse effects , Feasibility Studies , Female , Humans , Magnetic Resonance Imaging , Male , Melphalan/adverse effects , Middle Aged , Mitomycin/adverse effects , Neoadjuvant Therapy , Neoplasm Staging , Pain Measurement , Pelvic Neoplasms/radiotherapy , Pelvic Neoplasms/surgery , Radiotherapy Dosage , Remission Induction , Survival Rate , Tomography, X-Ray Computed
11.
Eur J Surg Oncol ; 31(8): 807-16, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15951150

ABSTRACT

AIMS: To review the development and current status of balloon catheter mediated hypoxic perfusion of abdomen, pelvis and liver for treatment of locally advanced malignancies. Within this context we focus on the addition of tumour necrosis factor-alpha (TNF) to these minimal invasive perfusion procedures. METHODS: A literature search on these topics was carried out in PubMed for indexed articles and in all issues of Regional Cancer Treatment. The findings were related to our own experiences. RESULTS: Hypoxic abdominal (HAP) and hypoxic pelvic perfusion (HPP) using balloon catheters, are currently applied modalities for treatment of a wide variety of abdominal and pelvic tumours, yet scientific validation of these procedures is poor. Following the results of several Phase I-II trials, both treatments are associated with severe systemic toxicity, significant morbidity and even mortality. The degree of systemic leakage associated with these procedures prohibits addition of TNF. For leakage free liver perfusion surgery is still required, as with current balloon catheter techniques it is not possible to perform leakage free isolated hypoxic hepatic perfusion (IHHP), using either orthograde or retrograde hepatic flow. Experimental and clinical observations suggest that within any perfusion setting, the utilization of TNF is only indicated for treatment of highly vascularised tumours and not for treatment of colorectal tumours. CONCLUSION: Balloon catheter technology in its present form does not provide adequate leakage control in any of these settings and is therefore associated with considerable toxicity. It is associated with poor response rates and cannot be considered in any setting as a standard of care.


Subject(s)
Abdominal Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Catheterization/methods , Chemotherapy, Cancer, Regional Perfusion/methods , Liver Neoplasms/drug therapy , Pelvic Neoplasms/drug therapy , Animals , Antineoplastic Agents/adverse effects , Catheterization/adverse effects , Chemotherapy, Cancer, Regional Perfusion/adverse effects , Humans , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/adverse effects
13.
Br J Cancer ; 91(8): 1610-3, 2004 Oct 18.
Article in English | MEDLINE | ID: mdl-15480435

ABSTRACT

Local adenoviral gene transfer can be performed by means of isolated hepatic perfusion (IHP). This methodology is a very effective and safe way to deliver adenoviral vectors. We studied the immune response after IHP. A decreased neutralising antibody formation was observed, offering possibilities for further research in the field of gene therapy in isolated perfusion settings.


Subject(s)
Adenoviridae/genetics , Antibodies, Viral/blood , Chemotherapy, Cancer, Regional Perfusion , Gene Transfer Techniques , Liver/virology , Transduction, Genetic , Animals , Antibody Formation , Genetic Vectors , Liver/pathology , Male , Neutralization Tests , Rats , Rats, Inbred Strains
14.
MAGMA ; 17(3-6): 296-302, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15480945

ABSTRACT

The objective of this study was to evaluate the potential of dynamic contrast-enhanced MRI for quantitative characterization of tumor microvessels and to assess the microvascular changes in response to isolated limb perfusion with TNF-alpha and melphalan. Dynamic contrast-enhanced MRI was performed in an experimental cancer model, using a macromolecular contrast medium, albumin-(Gd-DTPA)45. Small fragments of BN 175, a soft-tissue sarcoma, were implanted in 11 brown Norway (BN) rats. Animals were assigned randomly to a control (Haemaccel) or drug-treated group (TNF-alpha/melphalan). MRI was performed at baseline and 24 h after ILP. The transendothelial permeability (K(PS)) and the fractional plasma volume (fPV) were estimated from the kinetic analysis of MR data using a two-compartment bi-directional model. K(PS) and fPV decreased significantly in the drug-treated group compared to baseline (p<0.05). In addition, K(PS) post therapy was significantly lower (p<0.05) in the drug-treated group than in the control group. There was no significant difference in fPV between the drug-treated and the control group after therapy. Tumor microvascular changes in response to isolated limb perfusion can be determined after 24 h by dynamic contrast-enhanced MRI. The data obtained in this experimental model suggest possible applications in the clinical setting, using the appropriate MR contrast agents.


Subject(s)
Albumins , Contrast Media , Gadolinium DTPA , Image Enhancement/methods , Magnetic Resonance Imaging/methods , Melphalan/administration & dosage , Sarcoma, Experimental/diagnosis , Sarcoma, Experimental/drug therapy , Tumor Necrosis Factor-alpha/administration & dosage , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemotherapy, Cancer, Regional Perfusion/methods , Extremities/blood supply , Macromolecular Substances , Male , Prognosis , Rats , Rats, Inbred BN , Treatment Outcome
15.
Anticancer Res ; 24(4): 2243-8, 2004.
Article in English | MEDLINE | ID: mdl-15330168

ABSTRACT

In 1990 Clauss et al. first reported on a 44-kDa polypeptide, later called Endothelial Monocyte Activating Polypeptide II (EMAP II). This protein was discovered in the supernatant of Meth-A fibrosarcoma cells and was shown to enhance the induction of the procoagulant Tissue Factor (TF) on endothelial cells. Besides up-regulation of TF mRNA, EMAP II increases cellular receptors for TNF on endothelial cells, which is likely to enhance the predisposition of tumors to undergo thrombosis and hemorrhagic necrosis, once challenged with TNF. This feature enables EMAP II to up-regulate the TNF sensitivity of TNF-resistant tumors, an observation of importance in developing new approaches aimed at improving the efficacy of TNF as an anticancer treatment. We describe the potential additional effects of EMAP II, when used in combination with TNF, with regards to antitumor activity in the Isolated Limb Perfusion (ILP) setting. In addition, we describe our experimental data in human sarcoma, which also supports this hypothesis.


Subject(s)
Antineoplastic Agents/pharmacology , Cytokines/physiology , Neoplasm Proteins/physiology , Neoplasms/drug therapy , RNA-Binding Proteins/physiology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Cytokines/biosynthesis , Cytokines/genetics , Cytokines/pharmacology , Drug Synergism , Humans , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/pharmacology , Neoplasms/genetics , Neoplasms/metabolism , RNA-Binding Proteins/biosynthesis , RNA-Binding Proteins/genetics , RNA-Binding Proteins/pharmacology
16.
Eur J Surg Oncol ; 30(6): 671-80, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15256243

ABSTRACT

BACKGROUND: Developments in balloon catheter methodology have made hypoxic abdominal perfusion (HAP) with anti-tumour agents possible with only minimal invasive surgery. The initial reports on this modality and celiac axis stop-flow infusion for treatment of pancreatic cancer were very promising in terms of tumour response, median survival and pain reduction. Recent reports, however, have not been able to confirm these results and some have disputed the efficacy of these currently still applied treatment modalities. METHODS: Twenty-one patients with advanced pancreatic carcinoma were included in a phase I-II trial of HAP with MMC and Melphalan followed by celiac axis infusion (CAI) with the same agents six weeks later. Tumour response was assessed by abdominal-CT and by determining tumour markers. Effect on pain reduction was assessed by evaluation of pain registration forms. RESULTS: HAP resulted in augmented regional drug concentrations. One patient died after CAI due to acute mesenterial ischaemia. One agent-toxicity related death was observed in the phase-I study. Significant hematological toxicity was observed after HAP and CAI at MTD. No patients were considered resectable after treatment. Median survival after HAP was 6 months (range 1-29). Pain reduction was experienced by only 5/18 patients and was short-lived. CONCLUSION: In contrast to earlier reports HAP and CAI with MMC and Melphalan did not demonstrate any benefit in terms of tumour response, median survival and pain reduction, compared to less invasive treatment options. As this treatment was associated with significant toxic side-effects and even one procedure related death, we do not consider this a therapeutic option in patients with advanced pancreatic cancer.


Subject(s)
Antineoplastic Agents/administration & dosage , Chemotherapy, Cancer, Regional Perfusion , Melphalan/administration & dosage , Mitomycin/administration & dosage , Pancreatic Neoplasms/drug therapy , Aged , Balloon Occlusion/methods , Chemotherapy, Cancer, Regional Perfusion/methods , Female , Humans , Hypoxia , Infusions, Intra-Arterial/methods , Male , Middle Aged , Pain/drug therapy , Pain/etiology , Pain Measurement , Pancreatic Neoplasms/complications , Remission Induction , Treatment Outcome
17.
Eur J Surg Oncol ; 30(6): 699-707, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15256247

ABSTRACT

BACKGROUND: Addition of tumour necrosis factor-alpha (TNF) to hypoxic abdominal perfusion (HAP) and hypoxic pelvic perfusion (HPP) with chemotherapeutic agents for treatment of un-resectable malignancies may lead to similar enhanced anti-tumour effects as are observed when TNF is added to isolated limb perfusions (ILP) with Melphalan. Here, we validate the methodology of HAP and HPP using balloon catheter techniques, and investigate the distribution of TNF, Melphalan and Mitomycin C (MMC) over the regional and systemic blood compartments when applying these techniques. MATERIALS AND METHODS: Twelve pigs underwent HAP or HPP with TNF, Melphalan and MMC for 20 min. Throughout and after the procedures blood samples were obtained from hepatic, portal and systemic blood compartments and plasma concentrations of perfused agents were determined. RESULTS: We demonstrated that HAP and HPP result in temporary loco-regional concentration advantages of all perfused agents, although from start of perfusion significant systemic leakage occurred. CONCLUSION: On basis of these results it seems that the advantage in terms of regional plasma concentration of TNF may be insufficient for TNF-mediated effects to occur, making future addition of this cytokine to these procedures in the clinical setting questionable. The observed regional concentration advantages of MMC and Melphalan, however, warrant further studies on clinical application of these agents in both settings.


Subject(s)
Abdominal Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Chemotherapy, Cancer, Regional Perfusion/methods , Melphalan/administration & dosage , Mitomycin/administration & dosage , Pelvic Neoplasms/drug therapy , Tumor Necrosis Factor-alpha/administration & dosage , Animals , Antineoplastic Agents/analysis , Antineoplastic Agents/pharmacokinetics , Balloon Occlusion/methods , Hypoxia , Melphalan/blood , Melphalan/pharmacokinetics , Mitomycin/blood , Mitomycin/pharmacokinetics , Models, Animal , Swine , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/pharmacokinetics
18.
Br J Cancer ; 90(9): 1830-2, 2004 May 04.
Article in English | MEDLINE | ID: mdl-15208623

ABSTRACT

Here we show that Doxil has minimal antitumour activity in the isolated limb perfusion (ILP) setting and its activity was not enhanced by the addition of tumour necrosis factor (TNF). Doxil accumulation in tumour tissue was low and also not augmented by TNF. In contrast, activity of free conventional doxorubicin was enhanced by TNF. We conclude that application of Doxil in a TNF-based ILP is not a useful alternative to free conventional doxorubicin or melphalan.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Chemotherapy, Cancer, Regional Perfusion , Doxorubicin/pharmacology , Sarcoma/drug therapy , Tumor Necrosis Factor-alpha/pharmacology , Animals , Disease Models, Animal , Hindlimb/drug effects , Hindlimb/pathology , Humans , Male , Organ Culture Techniques , Rats
19.
Br J Cancer ; 88(2): 314-9, 2003 Jan 27.
Article in English | MEDLINE | ID: mdl-12610519

ABSTRACT

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-alpha) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-alpha in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-alpha contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastases model we studied three different tumours: colon carcinoma CC531, ROS-1 osteosarcoma and BN-175 soft-tissue sarcoma which exhibit different degrees of vascularisation. IHP was performed with melphalan with or without the addition of TNF-alpha. IHP with melphalan alone resulted, in all tumour types, in a decreased growth rate. However in the BN-175 tumour addition of TNF-alpha resulted in a strong synergistic effect. In the majority of the BN-175 tumour-bearing rats, a complete response was achieved. In vitro cytoxicity studies showed no sensitivity (CC531 and BN-175) or only minor sensitivity (ROS-1) to TNF-alpha, ruling out a direct interaction of TNF-alpha with tumour cells. The response rate in BN-175 tumour-bearing rats when TNF-alpha was coadministrated with melphalan was strongly correlated with drug accumulation in tumour tissue, as only in these rats a five-fold increased melphalan concentration was observed. Secondly, immunohistochemical analysis of microvascular density (MVD) of the tumour showed a significantly higher MVD for BN-175 tumour compared to CC531 and ROS-1. These results indicate a direct relation between vascularity of the tumour and TNF-alpha mediated effects. Assessment of the tumour vasculature of liver metastases would be a way of establishing an indication for the utility of TNF-alpha in this setting.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Antineoplastic Agents/administration & dosage , Liver Neoplasms, Experimental/blood supply , Liver Neoplasms, Experimental/metabolism , Melphalan/pharmacokinetics , Tumor Necrosis Factor-alpha/administration & dosage , Animals , Cell Division/drug effects , Chemotherapy, Cancer, Regional Perfusion/methods , Colonic Neoplasms/blood supply , Colonic Neoplasms/metabolism , Disease Models, Animal , Immunoenzyme Techniques , In Vitro Techniques , Liver Neoplasms, Experimental/secondary , Male , Microcirculation , Osteosarcoma/blood supply , Osteosarcoma/metabolism , Rats , Rats, Inbred BN , Sarcoma/blood supply , Sarcoma/metabolism , Tissue Distribution
20.
Int J Pharm ; 254(1): 55-8, 2003 Mar 18.
Article in English | MEDLINE | ID: mdl-12615409

ABSTRACT

Peptides with the RGD amino acid sequence show affinity for the alpha(v)beta(3) integrin, an integrin which is over-expressed on angiogenic endothelium and involved in cell adhesion. A peptide with the sequence ATWLPPR has been demonstrated to show affinity for the vascular endothelial growth factor (VEGF) receptor, a receptor involved in the proliferation of endothelial cells. By coupling these peptides to liposomes, these liposomes can serve as a site-specific drug delivery system to tumor endothelial cells in order to inhibit angiogenesis. In the present study we demonstrate that the coupling of cyclic RGD-peptides or ATWLPPR-peptides to the surface of PEG-liposomes results in binding of these liposomes to endothelial cells in vitro. Subsequent studies with RGD-peptide targeted liposomes in vivo also demonstrate specific binding to the tumor endothelium.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Drug Delivery Systems , Oligopeptides/chemistry , Polyethylene Glycols/chemistry , Angiogenesis Inhibitors/therapeutic use , Animals , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/metabolism , Cells, Cultured , Drug Carriers , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Flow Cytometry/instrumentation , Flow Cytometry/methods , Humans , In Vitro Techniques , Liposomes/chemistry , Mice , Microscopy, Confocal/instrumentation , Microscopy, Confocal/methods , Neovascularization, Pathologic/drug therapy , Peptide Fragments/administration & dosage , Peptide Fragments/chemistry , Receptors, Vascular Endothelial Growth Factor/metabolism , Time Factors , Transplants
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