Topotecan Vitreous Levels after Periocular or Intravenous Delivery in Rabbits: An Alternative for Retinoblastoma Chemotherapy

Carcaboso, Ángel M.; Bramuglia, Guillermo F.; Chantada, Guillermo; Fandiño, Adriana; Chiappetta, Diego Andrés; Dávila, María Teresa García de; Rubio, Modesto C.; Abramson, David H.

doi:10.1167/iovs.06-1152

Cited by 56 publications

(50 citation statements)

References 42 publications

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“…to investigate whether the retinal cancer stem-like cells display resistance to conventional chemotherapies, sphereforming cells and differentiated cells were exposed to carboplatin, a basic chemotherapeutic agent for retinoblastoma chemoreduction (1,30). Cell viable assays showed that sphereforming cells were dramatically resistant to carboplatin at different concentrations compared to differentiated cells (Fig.…”

Section: Sphere-forming Cells Display Chemoresistance To Carboplatinmentioning

confidence: 99%

Maintenance of retinal cancer stem cell-like properties through long-term serum-free culture from human retinoblastoma

Jiao

2011

Oncol Rep

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Abstract. previous studies have demonstrated that a small population of cancer stem cell-like cells exists in retinoblastoma. to provide a model for studying this population, we sought to establish a long-term culture from human retinoblastoma that have cancer stem cell-like properties. Fresh tumor tissue was digested and cultured in serum-free medium. tumor spheres formed and were passaged continuously. stem cell properties were examined through immunostaining, real-time quantitative rt-pCr and chemoresistance assay. tumorigenicity of the tumor sphere-forming cells was confirmed by xenograft experiments. Furthermore, we examined the expression of cell surface markers CD44 and CD133. tumor cells expanded as floating spheres for more than 30 passages. Sphere-forming cells overexpressed stem cell genes Oct-4, Nestin and Pax6. Immunostaining of spheres showed positivity for Nestin, pax6 and also ABCG2. In contrast, differentiated cells derived from these spheres expressed high levels of mature retinal cell markers MAp2, GFAp, recoverin, Opsin B and Nrl, and showed immunoreactivity for NF200, GFAp, recoverin and pKCα. Furthermore, both CD44 and CD133 were highly expressed in sphere-forming cells vs. differentiated cells. sphere-forming cells displayed higher chemoresistance to carboplatin as opposed to differentiated cells. Moreover, intraocular injection of as few as 2x10 3 sphere-forming cells into NOD/sCID mice gave rise to new tumors similar to the original patient tumors. these results revealed that the sphere-forming cells preserved their stem cell properties and tumorigenicity, even after longterm culture. this would be a suitable in vitro model to study cancer stem-like cells in retinoblastoma and to develop chemotherapeutic drugs and strategies.

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Section: Sphere-forming Cells Display Chemoresistance To Carboplatinmentioning

confidence: 99%

Maintenance of retinal cancer stem cell-like properties through long-term serum-free culture from human retinoblastoma

Jiao

2011

Oncol Rep

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“…This conclusion was supported by untreated eye!s AUC ratio of vitreous/plasma was similar to previous systemic pharmacokinetic studies [60]. To confirm that the contralateral eye is exposed by the system an additional postmortem pharmacokinetic experiment could be carried out as Carcaboso and colleagues [152]. Rats could be sacrificed just prior to the subconjunctival injection and samples would we harvested a couple hours after administration [152].…”

Section: Pharmacokinetic Studiessupporting

confidence: 68%

“…To confirm that the contralateral eye is exposed by the system an additional postmortem pharmacokinetic experiment could be carried out as Carcaboso and colleagues [152]. Rats could be sacrificed just prior to the subconjunctival injection and samples would we harvested a couple hours after administration [152]. If the contralateral eye exposed by the systemic circulation, we would expect the postmortem untreated eye to be drug free.…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

The Use of Preclinical Models to Improve the Treatment of Retinoblastoma

Nemeth¹

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“…As published previously [15][16][17][18] , topotecan can traverse the blood-retinal barrier into the vitreous humor or into the systemic circulation. In the present study, 2 μg of topotecan reached sufficient concentrations in plasma and in the contralateral vitreous humor.…”

Section: Discussionmentioning

confidence: 71%

“…Topotecan, a specific topoisomerase I inhibitor that is capable of producing lethal damage during the course of DNA replication 11,12 , has shown promising antitumor activity in pediatric solid tumors and leukemia [13][14][15] . The first study to examine the pharmacological penetration of topotecan into the vitreous cavity in animals demonstrated that periocular delivery of topotecan reached potentially active levels in the vitreous humor but sys- temic absorption accounted for most topotecan delivery 16 . Rapid drop-off in vitreous concentration of chemotherapeutic agent after periocular delivery is an impediment to efficacy.…”

Section: Introductionmentioning

confidence: 99%

Topotecan vitreous and plasma levels and retinal toxicity after transcorneal intravitreal delivery in healthy albino rabbits: Alternative retinoblastoma treatment

Darsova¹,

Pochop²,

Uhlı́k³

et al. 2012

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aim. To determine intravitreal and plasma concentrations and retinal toxicity after transcorneal intravitreal injection of 1 μg and 2 μg of topotecan (Hycamtin). Method. Twelve healthy albino rabbits were included in this in vivo experiment. Six anesthetized albino rabbits received a single transcorneal intravitreal injection of 1 μg (group A) or 2 μg (group B) of topotecan. Vitreous and blood samples were collected until 168 h. Left eyes were treated with the same volume of saline. Plasma and vitreous levels of topotecan were determined by high-performance liquid chromatography. Area under the plasma concentration time curve (AUC) was calculated using trapezoidal rule. Clinical evidence of toxicity was classified into four grades according to anatomical structures. Electroretinograms (ERGs) were recorded. Results. Time to maximum concentration was observed up to 2 h after drug injection in group A whereas up to 1 h in group B. Low levels of topotecan were detected in plasma in both groups and in the vitreous humor of the contralateral eye in group B. Topotecan levels (mean vitreous AUC in group A 2.55 μg/mL.h and in group B 5.338 μg/mL.h) were detectable up to 6 h in both groups. We observed following structural changes in rabbit eyes: corneal vascularization, cataract, hemophthalmus, choroidal edema and focal retinal atrophy. Abnormal ERGs were obtained. Conclusion. Our findings proved that transcorneal intravitreal administration of 1 μg and 2 μg of topotecan results in potentially cytotoxic intraocular concentrations. More studies are needed to establish the safety of topotecan for retinoblastoma in children.

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Topotecan Vitreous Levels after Periocular or Intravenous Delivery in Rabbits: An Alternative for Retinoblastoma Chemotherapy

Abstract: As a consequence of a favored passage across the blood-retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Transscleral entry in vivo was constrained by rapid clearance from the administration site.

Cited by 56 publications

References 42 publications

Maintenance of retinal cancer stem cell-like properties through long-term serum-free culture from human retinoblastoma

Maintenance of retinal cancer stem cell-like properties through long-term serum-free culture from human retinoblastoma

The Use of Preclinical Models to Improve the Treatment of Retinoblastoma

Topotecan vitreous and plasma levels and retinal toxicity after transcorneal intravitreal delivery in healthy albino rabbits: Alternative retinoblastoma treatment

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