Gemcitabine: vascular toxicity and prothrombotic potential

Dasanu, Constantin A

doi:10.1517/14740330802374262

Cited by 122 publications

(79 citation statements)

References 54 publications

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“…69 Certain chemotherapy agents (Table 3) have been associ ated with arterial thromboembolic events more than others: 5fluorouracil can decrease protein C levels and increase fibrinopeptide A levels 70 besides leading to endothelial damage and even endothelialindependent vasoconstriction via protein kinase C. 71 Gemcitabine has been associated with vascular events ranging from digital ischemia, VTE, thrombotic microangiopathy and systemic capillary leaks. 72 Cisplatin, a central component of several chemotherapeutic regimens, induces thrombosis by causing endothelial dam age, 73 activating platelets 74 and increasing monocyte tissue factor activity, 64 with a 12-17.6% risk 75 of strokes, recurrent peripheral arterial thromboembolic events and/or aortic thrombosis ( Figure 6). 76 Recently developed biologically targeted therapies such as bevacizumab, a vascular endothe lial growth factor (VEGF) inhibitor, have been associated with an increased risk of serious arterial thromboembolic events.…”

Section: Malignancy Treatment-related Thrombotic Events Chemotherapymentioning

confidence: 99%

Peripheral arterial ischemic events in cancer patients

2010

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Thromboembolic complications are the second leading cause of death in cancer patients. In contrast to the large body of literature on venous thromboembolism (VTE), relatively few reports have focused on the pathogenesis, incidence, management and outcomes of arterial thromboembolic events in patients with malignancy. The purpose of this article is to review the current literature on the etiology, mechanisms, and prognosis of arterial thromboembolic events in cancer patients and outline appropriate screening and management guidelines that may help lower the rates of morbidity and mortality related to these events.

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Section: Malignancy Treatment-related Thrombotic Events Chemotherapymentioning

confidence: 99%

Peripheral arterial ischemic events in cancer patients

2010

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“…Cerebral vasculitis has been reported as a result of PD-1 inhibition in a recent case report. 14 Of note, vasculitis (including cerebral vasculitis) has also been reported after gemcitabine and cisplatin exposure, 15,16 which the patient had previously received. However, the associated vasculitis in these reports occurred within months of drug exposure, and our patient's chemotherapy began over 7 years prior to presentation.…”

Section: Discussionmentioning

confidence: 99%

Clinical Reasoning: A 77-year-old man presenting with episodic expressive aphasia

et al. 2018

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A 77-year-old white man presented to the emergency department with a 1-week history of episodic expressive aphasia, lasting between 3 and 30 minutes and increasing in frequency. He denied any associated symptoms with the aphasia and between episodes returned to baseline. His medical history included psoriatic arthritis, remote biopsy-confirmed giant cell arteritis (GCA), and metastatic urothelial adenocarcinoma for which he was being treated with programmed death ligand 1 (PD-L1) checkpoint inhibitor therapy.Initial neurologic examination, including language evaluation, was normal. The patient's musculoskeletal examination revealed features of chronic arthritis with dorsal hand soft tissue atrophy and bony joint hypertrophy without active synovitis. There were no findings of cutaneous, cardiopulmonary, or gastrointestinal abnormalities.The patient's initial brain MRI (figure) showed acute infarction in the right internal capsule. MRI fluid-attenuated inversion recovery sequence was otherwise unremarkable with minimal evidence of small vessel disease. CT angiogram was striking for several focal areas of high-grade stenosis of the large intracranial vessels: the right internal carotid artery (ICA) terminus, the proximal left M1 segment, and the left A1 origin had near-complete stenosis. In contrast, the other intracranial and extracranial neck vessels were patent with minimal atherosclerotic disease.The patient was started on dual antiplatelet therapy (aspirin and Plavix) as well as high-dose statin for severe, symptomatic large vessel intracranial stenosis.Questions for consideration: 1. What are the potential causes of focal proximal stenosis of the large intracranial arteries? 2. Given this differential diagnosis, what additional workup is recommended? GO TO SECTION 2

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“…Gemcitabine, which is the most commonly used anticancer drug for treatment of PDAC, does not infrequently fail to provide the desired therapeutic effect (20)(21)(22)(23)(24)(25). Due to the many limitations and resistance factors of Gemcitabine, repeated attempts have been made in order to improve its therapeutic efficacy (20), also involving the use of liposomes.…”

Section: Discussionmentioning

confidence: 99%

“…Gemcitabine, despite being the standard treatment, is not devoid of limitations. Despite the inherent and acquired resistance mechanisms of pancreatic tumor cells towards gemcitabine, it has a very short half-life of around 15 min (20,21), induces systemic toxicity (22), and undergoes a rapid conversion into its inactive metabolite by cytidine deaminase in the blood stream (23). Another major limitation of gemcitabine is its need for active cellular uptake by the hENT1 receptors on the surface of pancreatic cancer cells.…”

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confidence: 99%

Development and In Vitro Characterization of a Gemcitabine-loaded MUC4-targeted Immunoliposome Against Pancreatic Ductal Adenocarcinoma

Urey

Hilmersson²,

Andersson³

et al. 2017

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Abstract. Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating disease. In the US and the European countries, PDAC is the fourth leading cause of cancer-related death (1, 2). Incidence and mortality rates follow closely (3, 4) and even though the relative 5-year survival rate has improved slightly over the last years, it is still as low as 7% (2). Surgically removing the primary tumor, i.e. resection, is the only potential cure for PDAC. However, at the time of diagnosis, only around 20% of patients are eligible for surgical resection (5), and even so, most patients will relapse within five years (6). For patients with non-resectable tumors, the main treatment option is chemotherapy which mainly consists of a gemcitabine-based regimen, either alone or in combination with other drugs (7).Mucins belong to a large family of high molecular weight glycoproteins characterized by long tandem repeat regions rich in serine, proline and threonine (8). Mucins are expressed by various epithelial cells (9) while the human mucin family consists of 21 members, MUC1-MUC21. Based on their functions, mucins are further divided into two different subclasses, as either secreted or membrane-bound mucins (10). Secreted mucins can be divided into gelforming (MUC2, MUC5AC, MUC5B, MUC6) and non-gelforming (MUC7) (9). The secreted mucins form a physical barrier of mucous gel for protection of epithelial cells in the respiratory and GI tracts. Membrane-bound mucins (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC13, MUC15, MUC16 and MUC17) are composed of a cytoplasmic tail and a transmembrane region and they contribute to the protective mucous gel through their single extracellular domain of O-glycosylated tandem repeats (8,10).In contrast to a healthy pancreas, which has weak or no mucin expression, pancreatic cancer is characterized by an aberrant expression of multiple mucins. During progression from normal pancreas to a malignant state, expression and glycosylation of both secreted and membrane-bound mucins are altered (10). Furthermore, altered expression of mucins is 6031 This article is freely accessible online.

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Gemcitabine: vascular toxicity and prothrombotic potential

Cited by 122 publications

References 54 publications

Peripheral arterial ischemic events in cancer patients

Peripheral arterial ischemic events in cancer patients

Clinical Reasoning: A 77-year-old man presenting with episodic expressive aphasia

Development and In Vitro Characterization of a Gemcitabine-loaded MUC4-targeted Immunoliposome Against Pancreatic Ductal Adenocarcinoma

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