Therapeutic Effect of Topical 5-Fluorouracil in Conjunctival Squamous Carcinoma Is Associated With Changes in Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases Expression

Iovieno, Alfonso; Lambìase, Alessandro; Moretti, Caterina; Perrella, Eleonora; Bombardieri, Stefano

doi:10.1097/ico.0b013e318190937d

Cited by 12 publications

(10 citation statements)

References 28 publications

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“…D5D- KD and DGLA), D5D- KD HCA-7 cells were treated with 5-FU alone or a combination of 5-FU and DGLA. 5-FU alone could downregulate the expressions of MMP-9, mesenchymal marker vimentin and EMT-inducing transcription factor snail and upregulate the expression of epithelial marker E-cadherin, consistent with other observations [4] , [49] , [50] , [51] , [52] . Further decreased expressions of MMP-9, vimentin, snail and further increased expression of E-cadherin were observed when D5D- KD HCA-7 cells were co-treated with DGLA and 5-FU ( Fig.…”

Section: Resultssupporting

confidence: 91%

Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells

Yang

Wang

et al. 2017

Redox Biology

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We recently reported that knockdown of delta-5-desaturase (a key enzyme that converts dihomo-γ-linolenic acid, DGLA, to the downstream ω-6 arachidonic acid) promotes formation of an anti-cancer byproduct 8-hydroxyoctanoic acid from cyclooxygenase (COX)-catalyzed DGLA peroxidation. 8-hydroxyoctanoic acid can exert its growth inhibitory effect on cancer cells (e.g. colon and pancreatic cancer) by serving as a histone deacetylase inhibitor. Since histone deacetylase inhibitors have been well-known to suppress cancer cell migration and invasion, we thus tested whether knockdown of delta-5-desaturase and DGLA treatment could also be used to inhibit cancer migration and invasion of colon cancer and pancreatic cancer cells. Wound healing assay, transwell assay and western blot were used to assess cell migration and invasion as well as the associated molecular mechanisms. Formation of threshold level of 8-hydroxyoctanoic acid was quantified from COX-catalyzed DGLA peroxidation in the cancer cells that overexpress COX-2 and their delta-5-desaturases were knocked down by shRNA transfection. Our results showed that knockdown of delta-5-desaturase along with DGLA supplement not only significantly inhibited cell migration, but also improved the efficacies of 5-flurouracil and gemcitabine, two frontline chemotherapy drugs currently used in the treatment of colon and pancreatic cancer, respectively. The molecular mechanism behind these observations is that 8-hydroxyoctanoic acid inhibits histone deacetylase, resulting in downregulation of cancer metastasis promotors, e.g., MMP-2 and MMP-9 as well as upregulation of cancer metastasis suppressor, e.g. E-cadherin. For the first time, we demonstrated that we could take the advantage of the common phenomenon of COX-2 overexpression in cancers to inhibit cancer cell migration and invasion. With the shifting paradigm of COX-2 cancer biology, our research outcome may provide us a novel cancer treatment strategy.

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Section: Resultssupporting

confidence: 91%

Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells

Yang

Wang

et al. 2017

Redox Biology

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“…Conjunctival intraepithelial neoplasia (CIN) is a frequent conjunctival tumor, while squamous cell carcinoma is the most frequent malignant tumor of the conjunctiva 1–6. Early manifestation is a small mass mimicking pterygium growing at or around the limbus, occurring in middle-aged patients 2–4…”

Section: Introductionmentioning

confidence: 99%

“…Topical interferon-α-2b has also been proposed as a possible medical alternative to surgical excision of primary or recurrent intraepithelial neoplasia 12. Topical chemotherapeutic agents, including topical mitomycin C (MMC), and 5-fluorouracil (5-FU), have been shown to be effective in treating conjunctival and corneal intraepithelial neoplasia alone, or as an adjunct to surgical excision,1,13–19 Although topical 5-FU has been shown to be effective in treating CIN, we propose an alternative dosing regimen that is as effective, better tolerated, and has reduced adverse side effects as compared with previous reported dosing regimens 17–19…”

Section: Introductionmentioning

confidence: 99%

5-Fluorouracil for the treatment of intraepithelial neoplasia and squamous cell carcinoma of the conjunctiva, and cornea

Al-Barrag¹

2010

OPTH

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Objective:To evaluate the efficacy and risks of complications of pulse dosing of topical 5-fluorouracil (5-FU) in the treatment of corneal intraepithelial neoplasia (CIN), and conjunctival squamous cell carcinoma (SCC).Design:Prospective, noncomparative case series.Participants:Fifteen patients with histological evidence CIN or SCC of the conjunctiva and cornea were identified by tumor biopsy.Methods:All patients clinically evident of CIN, or SCC were evaluated, with maximum 30 months of follow-up were treated with pulsed dosing of 1% 5-FU. Treatment cycles were defined as four times per day for 4 days using the medication followed by 30 days without medication. The number of initial treatment was six cycles.Results:The mean age of the 15 patients was 50.8 years (range 25–78 years). Excision biopsy proved seven cases as CIN, and eight cases as locally invasive SCC. All patients remained disease free with a mean follow-up of 14.53 months (range 6–30 months). Additional chemotherapy was given after the initial treatment cycles, only for one case. 5-FU caused mild temporary local irritation, but no long-term intraocular or extra ocular complications.Conclusions:Adjuvant 1% topical 5-FU appears to be effective in the prevention of recurrence of conjunctival or corneal CIN and SCC after excision biopsy. Our results indicate that at least six cycles of topical 1% 5-FU is required to prevent local recurrence in the long term. It is well-tolerated and an effective method of treatment. No complications that would preclude use of our dose regimen were noted.

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“…The FOLFOX chemotherapy regime consists of folinic acid, 5-FU and oxaliplatin agents. Exposure to 5-FU, which is an antimetabolite, has also been shown to decrease MMP production in rabbit flexor tendon fibroblasts [13], as well as in conjunctival squamous cell carcinoma [14]. Oxaliplatin, which is a platinum compound, has also demonstrated inhibition of MMP production [15,16].…”

Section: Discussionmentioning

confidence: 99%

Bilateral Simultaneous Frozen Shoulder: A Possible Adverse Event of the Folfox Chemotherapy Regime?

Patel

Curtis

2012

Shoulder & Elbow

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A 51-year-old female underwent an uncomplicated resection of a sigmoid adenocarcinoma. Postoperatively, 12 cycles of the FOLFOX chemotherapy regime were completed, consisting of a combination of folinic acid, 5-fluorouracil and oxaliplatin over a 24 week period. Following chemotherapy, the patient developed simultaneous adhesive capsulitis in both shoulder joints, as radiologically confirmed by magnetic resonance imaging. Bilateral adhesive capsulitis is rare and usually associated with a systemic cause. This case highlights a possible previously unreported association between the widely used FOLFOX chemotherapy regime and bilateral adhesive capsulitis. Oncologists and orthopaedic surgeons should be aware of such presentations in FOLFOX patients to facilitate prompt investigation and management. INTRODUCTIONAdhesive capsulitis of the shoulder (or 'frozen shoulder') manifests as chronic pain and gradual deterioration in both passive and active glenohumeral movement as a result of extensive fibrosis and eventual contracture of the glenohumeral joint capsule [1]. It is a relatively common condition, with a reported prevalence of 2% to 5%, typically affecting women aged between 40 years and 60 years [2]. The progression of the disease manifests in three widely recognized stages. In the first stage (freezing stage), early inflammatory changes and reactive synovitis lead to severe shoulder pain and restricted range of motion. The second stage (frozen stage) presents with marked stiffness of the shoulder with significant restriction in everyday activities as a result of pathological capsular thickening. The final stage (thawing stage) is the slow return of normal range of movement and strength.Bilateral adhesive capsulitis can occur in up to 20% of patients; however, simultaneous bilateral pathology is very uncommon, with the majority of cases being associated with an underlying systemic cause [3]. A previous study by Hutchinson et al. demonstrated a strong association between adhesive capsulitis and a synthetic matrix metalloproteinase (MMP) inhibitor called Marimastat (British Biotech, Oxford, UK), which is used for inoperable gastric carcinoma [4]. To date, no other chemotherapy regimes have been linked with adhesive capsulitis pathology. A significant relationship has also been shown between unilateral adhesive capsulitis and human immunodeficiency virus patients on highly-active antiretroviral therapy, particularly protease inhibitors [5,6].The FOLFOX chemotherapy regime is widely recognized for the management of advanced colorectal carcinoma. In particular, it

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Therapeutic Effect of Topical 5-Fluorouracil in Conjunctival Squamous Carcinoma Is Associated With Changes in Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases Expression

Abstract: In our case report, we have shown that gelatinase and TIMP-1 are unregulated in conjunctival SCC and can be monitored as a marker of response to topical chemotherapy. Further studies are required to define the role of MMPs in growth and resolution of ocular tumors.

Cited by 12 publications

References 28 publications

Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells

Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells

5-Fluorouracil for the treatment of intraepithelial neoplasia and squamous cell carcinoma of the conjunctiva, and cornea

Bilateral Simultaneous Frozen Shoulder: A Possible Adverse Event of the Folfox Chemotherapy Regime?

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