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Peng T. Khaw - One of the best experts on this subject based on the ideXlab platform.
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National survey of Antimetabolite use in glaucoma surgery in the United Kingdom
The British journal of ophthalmology, 2004Co-Authors: D. Siriwardena, Beth Edmunds, Richard Wormald, Peng T. KhawAbstract:Aims: To assess the pattern of use of Antimetabolites in trabeculectomy surgery by all consultant ophthalmologists in the United Kingdom. Methods: A postal questionnaire of 12 questions regarding Antimetabolite use in trabeculectomy surgery was sent to all 749 consultant ophthalmologists in the United Kingdom. The consultants were asked to estimate the number of trabeculectomies they performed per year, how often they used 5-fluorouracil (5-FU) in primary and redo surgery, their usual method of administration of 5-FU, how often they used mitomycin (MMC) in primary and redo surgery, and their usual dosage regimen of MMC. Factors that influenced the decision to use or not use Antimetabolites were also assessed. Results: The response rate of consultants returning the questionnaire was 82% (615 out of 749); 87% (533) of these consultants perform trabeculectomy surgery. Of these 533 consultants, 98 (18%) never use an Antimetabolite. Most consultants (82%) use Antimetabolites, but use them infrequently (only 9% using Antimetabolites in more than half their cases). The preferred Antimetabolite is 5-FU rather than MMC. Of the 435 consultants performing trabeculectomy surgery and using Antimetabolites, 402 (93%) use 5-FU and 179 (41%) use MMC. Various factors influenced the decision to use or not use an Antimetabolite, but experience of complications associated with their use was a factor for 34% of consultants. Conclusion: The use of Antimetabolites, particularly MMC, in the United Kingdom is much less than in America or Japan, where trabeculectomy with MMC is the surgical procedure preferred by glaucoma specialists.
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effects of Antimetabolite induced cellular growth arrest on fibroblast fibroblast interactions
Experimental Eye Research, 1999Co-Authors: Julie T Daniels, Peng T. Khaw, Jonathan G. Crowston, Nicholas L OcclestonAbstract:The use of single five-minute applications of Antimetabolites during glaucoma filtration surgery has significantly reduced the occurrence of post-operative scarring and bleb failure. However, surgery for some patients is still unsuccessful, despite the use of antiproliferative agents, due to formation of scar tissue at the drainage site. It is not known if cells growth arrested in the treated area with a single application of Antimetabolites influence the activity of adjacent non-treated cells. We hypothesise that the activity of non-treated cells recruited to the wound site may be involved in post-operative scarring. The aim of this study was to investigate the effects of Antimetabolite induced cellular growth arrest on cell-cell interactions using in vitro techniques.Tenon's capsule fibroblast cultures were growth arrested by exposure for 5 minutes to mitomycin-C (0.001, 0.01 and 0.1 mg ml-1), 5-fluorouracil (0.25, 2.5 and 25 mg ml-1) or phosphate buffered saline (PBS). Following a period of serum-starvation, conditioned media (CM) were subsequently collected from the cells at intervals up to 29 days post-treatment. Correction for cell number was made prior to supplementation of serum-free medium with CM. CM were assessed for ability to support or inhibit normal non-treated fibroblast proliferation, migration and collagen contraction. Conditioned media collected from cells growth arrested with MMC or 5FU stimulated normal fibroblast proliferation, migration and collagen contraction in excess of non-conditioned serum-free medium. Peaks of fibroblast activity in CM differed according to which drug and concentration had originally been given to the treated cells. This study has demonstrated that CM collected from fibroblasts treated for 5 minutes with a range of concentrations of Antimetabolites can differentially influence normal non-treated fibroblast activity. This in vitro data suggests that despite entering growth arrest, fibroblasts may still influence the behaviour of other cells via soluble mediators. They may have implications in the clinical setting, in that it may not be sufficient to suppress proliferation alone to prevent fibroblast behaviour associated with scarring after glaucoma filtration surgery.
Stanton L. Gerson - One of the best experts on this subject based on the ideXlab platform.
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Abstract #3765: Induction of uracil DNA glycosylase (UDG) in human cancer cells in response to Antimetabolites combined with methoxyamine
Cancer Research, 2009Co-Authors: Lachelle D. Weeks, Alina Bulgar, Jon R. Donze, Yanling Miao, Lili Liu, Stanton L. GersonAbstract:Antimetabolites are used in cancer therapy to disrupt nucleic acid, RNA and DNA production. We have previously reported that methoxyamine (MX), which inhibits BER by binding and stabilizing abasic (AP) sites after glycosylase removal of an abnormal base, enhances the cytotoxicity of the Antimetabolite fludarabine, a purine analog, in human leukemia cells. The MX-potentiated cytotoxicity was also observed in lung, breast and colon cancer cells after treatment with pemetrexed, an antifolate Antimetabolite. Cytotoxicity of pemetrexed has been attributed to thymidylate synthetase (TS) inhibition which causes reduction of dTTP levels with a concomitant rise in dUTP. In this milieu, uracil is aberrantly incorporated into the genome, removed by uracil DNA glycosylase (UDG), and reincorporated during DNA replication. To determine the role of base excision repair (BER) in fludarabine and pemetrexed activity, we examined the effects of Antimetabolite therapy in combination with MX on the induction of BER proteins and BER protein activity in established human cancer cell lines. Human leukemia cells (Jurkat) were treated with fludarabine (5uM) alone or in combination with MX treatment (3mM). Immunoblot results indicated modest enhancement of UDG protein level following fludarabine treatment (~1.5 fold) and more significant enhancement with MX adjunct therapy (2-3 fold). RT-PCR similarly revealed induction of UDG transcript level (2-3 fold) in response to fludarabine and MX treatment. Human lung cancer cells (H460 and A549) were treated with pemetrexed (100-400uM) alone and in combination with MX (6mM) for 24 hr. Significant induction of UDG protein was observed in cells treated with pemetrexed and MX, resulting in a 2-fold increase in UDG enzymatic activity measured by UDG cleavage assay. Meanwhile, a concomitant increase in level of \#947;H2AX and cleaved PARP was seen in the cells. Therefore, UDG induction was a compensatory mechanism of cell protection from DNA damage when BER was blocked by MX. However, increased UDG activity was capable of producing more AP sites, which were bound by MX. In this way, pemetrexed induced imbalance of nucleotide pool results in futile cycles between incorporation of uracil and the removing process by UDG, leading to cell death. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3765.
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abstract 3765 induction of uracil dna glycosylase udg in human cancer cells in response to Antimetabolites combined with methoxyamine
Cancer Research, 2009Co-Authors: Lachelle D. Weeks, Alina Bulgar, Jon R. Donze, Yanling Miao, Lili Liu, Stanton L. GersonAbstract:Antimetabolites are used in cancer therapy to disrupt nucleic acid, RNA and DNA production. We have previously reported that methoxyamine (MX), which inhibits BER by binding and stabilizing abasic (AP) sites after glycosylase removal of an abnormal base, enhances the cytotoxicity of the Antimetabolite fludarabine, a purine analog, in human leukemia cells. The MX-potentiated cytotoxicity was also observed in lung, breast and colon cancer cells after treatment with pemetrexed, an antifolate Antimetabolite. Cytotoxicity of pemetrexed has been attributed to thymidylate synthetase (TS) inhibition which causes reduction of dTTP levels with a concomitant rise in dUTP. In this milieu, uracil is aberrantly incorporated into the genome, removed by uracil DNA glycosylase (UDG), and reincorporated during DNA replication. To determine the role of base excision repair (BER) in fludarabine and pemetrexed activity, we examined the effects of Antimetabolite therapy in combination with MX on the induction of BER proteins and BER protein activity in established human cancer cell lines. Human leukemia cells (Jurkat) were treated with fludarabine (5uM) alone or in combination with MX treatment (3mM). Immunoblot results indicated modest enhancement of UDG protein level following fludarabine treatment (~1.5 fold) and more significant enhancement with MX adjunct therapy (2-3 fold). RT-PCR similarly revealed induction of UDG transcript level (2-3 fold) in response to fludarabine and MX treatment. Human lung cancer cells (H460 and A549) were treated with pemetrexed (100-400uM) alone and in combination with MX (6mM) for 24 hr. Significant induction of UDG protein was observed in cells treated with pemetrexed and MX, resulting in a 2-fold increase in UDG enzymatic activity measured by UDG cleavage assay. Meanwhile, a concomitant increase in level of \#947;H2AX and cleaved PARP was seen in the cells. Therefore, UDG induction was a compensatory mechanism of cell protection from DNA damage when BER was blocked by MX. However, increased UDG activity was capable of producing more AP sites, which were bound by MX. In this way, pemetrexed induced imbalance of nucleotide pool results in futile cycles between incorporation of uracil and the removing process by UDG, leading to cell death. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3765.
Lachelle D. Weeks - One of the best experts on this subject based on the ideXlab platform.
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Abstract #3765: Induction of uracil DNA glycosylase (UDG) in human cancer cells in response to Antimetabolites combined with methoxyamine
Cancer Research, 2009Co-Authors: Lachelle D. Weeks, Alina Bulgar, Jon R. Donze, Yanling Miao, Lili Liu, Stanton L. GersonAbstract:Antimetabolites are used in cancer therapy to disrupt nucleic acid, RNA and DNA production. We have previously reported that methoxyamine (MX), which inhibits BER by binding and stabilizing abasic (AP) sites after glycosylase removal of an abnormal base, enhances the cytotoxicity of the Antimetabolite fludarabine, a purine analog, in human leukemia cells. The MX-potentiated cytotoxicity was also observed in lung, breast and colon cancer cells after treatment with pemetrexed, an antifolate Antimetabolite. Cytotoxicity of pemetrexed has been attributed to thymidylate synthetase (TS) inhibition which causes reduction of dTTP levels with a concomitant rise in dUTP. In this milieu, uracil is aberrantly incorporated into the genome, removed by uracil DNA glycosylase (UDG), and reincorporated during DNA replication. To determine the role of base excision repair (BER) in fludarabine and pemetrexed activity, we examined the effects of Antimetabolite therapy in combination with MX on the induction of BER proteins and BER protein activity in established human cancer cell lines. Human leukemia cells (Jurkat) were treated with fludarabine (5uM) alone or in combination with MX treatment (3mM). Immunoblot results indicated modest enhancement of UDG protein level following fludarabine treatment (~1.5 fold) and more significant enhancement with MX adjunct therapy (2-3 fold). RT-PCR similarly revealed induction of UDG transcript level (2-3 fold) in response to fludarabine and MX treatment. Human lung cancer cells (H460 and A549) were treated with pemetrexed (100-400uM) alone and in combination with MX (6mM) for 24 hr. Significant induction of UDG protein was observed in cells treated with pemetrexed and MX, resulting in a 2-fold increase in UDG enzymatic activity measured by UDG cleavage assay. Meanwhile, a concomitant increase in level of \#947;H2AX and cleaved PARP was seen in the cells. Therefore, UDG induction was a compensatory mechanism of cell protection from DNA damage when BER was blocked by MX. However, increased UDG activity was capable of producing more AP sites, which were bound by MX. In this way, pemetrexed induced imbalance of nucleotide pool results in futile cycles between incorporation of uracil and the removing process by UDG, leading to cell death. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3765.
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abstract 3765 induction of uracil dna glycosylase udg in human cancer cells in response to Antimetabolites combined with methoxyamine
Cancer Research, 2009Co-Authors: Lachelle D. Weeks, Alina Bulgar, Jon R. Donze, Yanling Miao, Lili Liu, Stanton L. GersonAbstract:Antimetabolites are used in cancer therapy to disrupt nucleic acid, RNA and DNA production. We have previously reported that methoxyamine (MX), which inhibits BER by binding and stabilizing abasic (AP) sites after glycosylase removal of an abnormal base, enhances the cytotoxicity of the Antimetabolite fludarabine, a purine analog, in human leukemia cells. The MX-potentiated cytotoxicity was also observed in lung, breast and colon cancer cells after treatment with pemetrexed, an antifolate Antimetabolite. Cytotoxicity of pemetrexed has been attributed to thymidylate synthetase (TS) inhibition which causes reduction of dTTP levels with a concomitant rise in dUTP. In this milieu, uracil is aberrantly incorporated into the genome, removed by uracil DNA glycosylase (UDG), and reincorporated during DNA replication. To determine the role of base excision repair (BER) in fludarabine and pemetrexed activity, we examined the effects of Antimetabolite therapy in combination with MX on the induction of BER proteins and BER protein activity in established human cancer cell lines. Human leukemia cells (Jurkat) were treated with fludarabine (5uM) alone or in combination with MX treatment (3mM). Immunoblot results indicated modest enhancement of UDG protein level following fludarabine treatment (~1.5 fold) and more significant enhancement with MX adjunct therapy (2-3 fold). RT-PCR similarly revealed induction of UDG transcript level (2-3 fold) in response to fludarabine and MX treatment. Human lung cancer cells (H460 and A549) were treated with pemetrexed (100-400uM) alone and in combination with MX (6mM) for 24 hr. Significant induction of UDG protein was observed in cells treated with pemetrexed and MX, resulting in a 2-fold increase in UDG enzymatic activity measured by UDG cleavage assay. Meanwhile, a concomitant increase in level of \#947;H2AX and cleaved PARP was seen in the cells. Therefore, UDG induction was a compensatory mechanism of cell protection from DNA damage when BER was blocked by MX. However, increased UDG activity was capable of producing more AP sites, which were bound by MX. In this way, pemetrexed induced imbalance of nucleotide pool results in futile cycles between incorporation of uracil and the removing process by UDG, leading to cell death. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3765.
Beth Edmunds - One of the best experts on this subject based on the ideXlab platform.
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A randomised, prospective study comparing trabeculectomy with viscocanalostomy with adjunctive Antimetabolite usage for the management of open angle glaucoma uncontrolled by medical therapy
British Journal of Ophthalmology, 2004Co-Authors: D P S O’brart, M Shiew, Beth EdmundsAbstract:Aims: To compare trabeculectomy with viscocanalostomy augmented with adjunctive Antimetabolite use for the control of intraocular pressure (IOP) in open angle glaucoma (OAG). Methods: 45 patients (50 eyes) with uncontrolled OAG were randomised to either trabeculectomy (25 eyes) or a viscocanalostomy technique (25 eyes). Preoperatively, all eyes were graded in terms of risk factors for drainage failure and were given intraoperative Antimetabolites (5-fluorouracil 25 mg/ml (5-FU), mitomycin C (MMC) 0.2 mg/ml and 0.4 mg/ml) according to a standard protocol. Results: There were no significant differences between the groups in age, sex, type of OAG, preoperative medications, risk factors for drainage failure, and preoperative IOP. Mean follow up was 20 months (range 3–24 months). It was 12 months or longer in all eyes, except two lost to follow up at 3 months. At 12 months, complete success (IOP Conclusion: In terms of complete success and number of antiglaucomatous medications required postoperatively, IOP control appears to be better with trabeculectomy. Viscocanalostomy is associated with fewer early transient postoperative complications.
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National survey of Antimetabolite use in glaucoma surgery in the United Kingdom
The British journal of ophthalmology, 2004Co-Authors: D. Siriwardena, Beth Edmunds, Richard Wormald, Peng T. KhawAbstract:Aims: To assess the pattern of use of Antimetabolites in trabeculectomy surgery by all consultant ophthalmologists in the United Kingdom. Methods: A postal questionnaire of 12 questions regarding Antimetabolite use in trabeculectomy surgery was sent to all 749 consultant ophthalmologists in the United Kingdom. The consultants were asked to estimate the number of trabeculectomies they performed per year, how often they used 5-fluorouracil (5-FU) in primary and redo surgery, their usual method of administration of 5-FU, how often they used mitomycin (MMC) in primary and redo surgery, and their usual dosage regimen of MMC. Factors that influenced the decision to use or not use Antimetabolites were also assessed. Results: The response rate of consultants returning the questionnaire was 82% (615 out of 749); 87% (533) of these consultants perform trabeculectomy surgery. Of these 533 consultants, 98 (18%) never use an Antimetabolite. Most consultants (82%) use Antimetabolites, but use them infrequently (only 9% using Antimetabolites in more than half their cases). The preferred Antimetabolite is 5-FU rather than MMC. Of the 435 consultants performing trabeculectomy surgery and using Antimetabolites, 402 (93%) use 5-FU and 179 (41%) use MMC. Various factors influenced the decision to use or not use an Antimetabolite, but experience of complications associated with their use was a factor for 34% of consultants. Conclusion: The use of Antimetabolites, particularly MMC, in the United Kingdom is much less than in America or Japan, where trabeculectomy with MMC is the surgical procedure preferred by glaucoma specialists.
PT Khaw - One of the best experts on this subject based on the ideXlab platform.
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Australia and New Zealand survey of Antimetabolite and steroid use in trabeculectomy surgery
J GLAUCOMA, 2008Co-Authors: PT KhawAbstract:Aim: To assess the pattern Of use of Antimetabolites and steroids in trabeculectomy surgery among consultant ophthalmologists in Australia and New Zealand.Method: A postal questionnaire of 25 questions regarding current glaucoma practices and Antimetabolite and steroid use in trabeculectomy Surgery was sent to all practicing Australian and New Zealand Fellows of the Royal Australia and New Zealand College of Ophthalmologists in July 2005. The second half of the survey consisted of questions on the number of trabeculectomies performed per year, topical steroid use, the type of Antimetabolite used, and assessment of factors that may influence the decision to use them, The results were cross-tabulated according to state/country, years practicing, type of practice, and being a glaucoma subspecialist (GSS).Results: The overall response rate was 78% (627 out of 808). Ninety-one percent stated that they managed glaucoma of which 65% stated that they perform trabeculectomy Surgery and 16% considered themselves as a GSS. In 2004, 75% of ophthalmologists performed less than 10 trabeculectomies. Sixty-one percent used an Antimetabolite in trabeculectomy surgery of which 5-fluorouracil was used 51% (intraoperatively) and 24% (postoperatively). Mitomycin C was used in 12% and 0.2mg/mL was the most commonly used concentration for 2 or 3 minutes. Fifty-four percent used postoperative steroids in a primary trabeculectomy for I to 2 months with 48% of GSSs using it for 2 to 3 months. Forty-eight percent to 96% would use an Antimetabolite in patients with risk factors for conjunctival scarring.Conclusions: This survey shows a wide range of the use of Antimetabolites and steroids in trabeculectomy surgery with 5-fluorouracil being most commonly used. GSSs and young ophthalmologists would use Antimetabolites more often and postoperative steroids for longer. This survey allows ophthalmologists to compare their own practices with those of their colleagues in Australia and the United Kingdom.
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correction of lower eyelid retraction in thyroid eye disease a randomised controlled trial of retractor tenotomy with adjuvant Antimetabolite versus scleral graft
British Journal of Ophthalmology, 1998Co-Authors: J M Olver, PT Khaw, Geoffrey E Rose, J R O CollinAbstract:Background/aims—Lower eyelid retraction in thyroid eye disease contributes to ocular discomfort and an unsightly appearance, especially if asymmetrical. The use of donor scleral grafts is eVective in lengthening the lower eyelids but carries a risk of virus transmission. Other techniques, including those which do not use grafts, need to be compared with scleral grafts. Recurrent retraction is a recognised complication of thyroid eyelid surgery; therefore, the authors investigated the use of Antimetabolites to reduce postoperative fibrosis. Methods—In this prospective randomised controlled trial of 25 patients (35 eyelids), the use of donor sclera in 20 lower eyelids (13 patients) was compared with partial tenotomy of the anterior part of the lower eyelid retractors (ALER) with adjuvant peroperative Antimetabolite in 15 lower eyelids (12 patients). A 5 minute peroperative application of either 5-fluorouracil (25 mg/ml) in nine lower eyelids (eight patients) or mitomycin C (0.2 mg/ml) in six lower eyelids (four patients) was used to focally inhibit fibroblasts. Follow up ranged from 3 to 18 months (mean 7.8). Results—One month after surgery the results of both groups were similar. However, at 3 months after surgery the results of scleral grafting were better than tenotomy with Antimetabolites: 3/12 patients (25%) treated with tenotomy and adjuvant Antimetabolite required subsequent surgery using grafts for correction of recurrent retraction. There were no significant complications associated with the use of Antimetabolites in the eyelid in the doses used in this study. Conclusions—This randomised prospective trial shows that donor scleral grafts were more eVective in the long term than partial tenotomy with adjuvant Antimetabolite in the correction of lower eyelid retraction associated with thyroid eye disease. The use of peroperative Antimetabolites in the lower eyelid was safe. (Br J Ophthalmol 1998;82:174‐180)