Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer

Abstract. Elevated expression of tissue factor (tF) has been associated with an increased risk of thrombosis in the majority of cancers. moreover, treatment of cancer patients with low molecular weight heparin (lmWh) appears to have beneficial effects that reach beyond controlling the immediate hypercoagulable state. in this study, we investigated the influence of the treatment of cancer cells with LMWH (0-2,000 µg/ml) on cell invasiveness and migration in cancer cell lines from five separate tissues; pancreatic, breast, colocarcinoma, ovarian and melanoma. the rate of cell invasion across collagen iV-coated membranes was suppressed in all cell lines tested on incubation with 2,000 µg/ml lmWh, but Bxpc-3 and mda-mB-231 cells also responded to the lowest concentration of 20 µg/ml lmWh. Furthermore, the rate of cell migration was reduced to varying extents in all of the cell lines tested on incubation with 20 µg/ml or higher concentrations of lmWh. the decrease in the rates of invasion and migration also strongly correlated with the reduction in tF protein expression and tF activity in these cells following incubation with lmWh. moreover, the lmWh-mediated decreases in cellular invasion in the most affected cell lines (Bxpc-3 and mda-mB-231) were restored by transfection of the cells with the mammalian pcmV-xl5-tF expression vector allowing independent overexpression of tF. in conclusion, lmWh appears to suppress the rate of cancer cell invasion and migration in vitro, through a mechanism that is at least in part dependent on the tF protein expression and activity in cancer cells. Introductionthe association between increased tissue factor (tF) expression and aggressiveness of cancer is well established. the expression of tF has been correlated with the histological grade of tumours (1), and the up-regulation of tF expression in cancer cells occurs early during the disease (2). Furthermore, the ability of tF to induce cellular cancer cell proliferation, migration and invasion has been documented (3-7). heparin treatment of cancer patients has been used as a means of controlling the risk of thrombotic episodes (8), and low molecular weight heparin (lmWh) has been reported to be suitable for the regulation of the procoagulant action of tF (9). there is data that incubation of cancer cell lines with lmWh results in the suppression of tF expression. additionally, we previously reported a reduction in the levels of circulating tF in the plasma from pancreatic cancer patients receiving prophylactic lmWh (daltaparin), compared to those not receiving the treatment (10). in this study, we further demonstrated the ability of lmWh to reduce the level of tF antigen and activity in cell lines from five separate tissues; BxPC-3 (pancreatic cancer), mda-mB-231 (breast cancer), loVo (colorectal cancer), SKOV-3 (ovarian cancer) and a375 (melanoma). crucially, we report that the incubation of these cancer cell lines with lmWh (20-2,000 µg/ml) reduces cellular invasion and migration through a tF-mediated mechanism in vitro. Material...

show abstract

“…The benefits of LMWH in the treatment of cancer patients have previously been reported (11,12). Moreover, the beneficial A B Figure 1.…”

Section: Discussionmentioning

confidence: 90%

Low molecular weight heparin suppresses tissue factor-mediated cancer cell invasion and migration in vitro

Ettelaie¹,

Fountain²,

Collier³

et al. 2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…Approximately 20% of patients diagnosed with pancreatic adenocarcinoma develop venous thromboembolism, contributing to the poor prognosis of this disease. A small phase II trial suggested longer survival with the addition of low molecular weight heparin (LMWH) to chemotherapy [70]. In that study, 69 patients received standard gemcitabine with or without LMWH (nadroparine calcium, 2,850 IU/day until disease progression).…”

Section: Multidrug Regimensmentioning

confidence: 99%

Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty?

2008

View full text Add to dashboard Cite

Pancreatic cancer is the fourth most common cause of adult cancer death in the U.S. The high mortality rate from pancreatic cancer is a result of the high incidence of metastatic disease at the time of diagnosis, an often fulminant clinical course, and the lack of adequate systemic therapies. Unfortunately, only 5%-25% of patients present with tumors amenable to resection. The median diseasefree survival interval following resection for operable pancreatic cancer is 13.4 months for patients treated with adjuvant gemcitabine and 6.9 months for untreated patients. A much higher percentage of patients present with metastatic disease (40%-45%) or locally advanced disease (40%), and have median survival times of 3-6 months or 8 -12 months, respectively. The frustrating lack of significant clinical advancements in the treatment of metastatic pancreatic cancer remains one of medical oncology's biggest disappointments. The past decade-long frustration has resulted in regulators, investigators, and practicing oncologists gradually lowering their standards/expectations with regard to interpreting clinical trials. Two of the more important examples of this include the approval of gemcitabine plus erlotinib and the use of a progressionfree survival advantage to defend the use of gemcitabine plus oxaliplatin. Given the marginal benefit of systemic antineoplastics, a scholarly review inclusive of other palliative strategies will help oncologists optimize the care of pancreatic cancer patients. This article examines the existing evidence in support of a role for palliative therapy in metastatic pancreatic cancer, describes recent developments with newer chemotherapeutic and molecular-targeted agents, and explores future study designs. The Oncologist 2008;13:562-576

show abstract

“…The results showed a better mean time to progression in the group receiving prophylaxis (6.0+/-0.9 months) when compared to control group (3.0+/-1.5 months) (p=0.0001). Also median overall survival time for the nadoparin group was 9.0+/-1.9 months compared to 4.0+/-0.4 months (p=0.0034) in the control group (Icli et al, 2007).…”

Section: Prophylaxis Of Venous Trombosismentioning

confidence: 80%

Coagulation Disorders in Pancreatic Cancer

Albu¹,

Gheban²,

Grad³

et al. 2012

Pancreatic Cancer - Clinical Management

View full text Add to dashboard Cite

Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer

Abstract: Addition of LMWH to GEM plus CDDP combination significantly improved the response and survival in patients with APC and the current schedule deserves to be tested in phase III trials.

Cited by 91 publications

References 25 publications

Low molecular weight heparin suppresses tissue factor-mediated cancer cell invasion and migration in vitro

Low molecular weight heparin suppresses tissue factor-mediated cancer cell invasion and migration in vitro

Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty?

Coagulation Disorders in Pancreatic Cancer

Contact Info

Product

Resources

About