Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study
| Autor: | Janene Pierce, Kelli L. Boyd, Debra L. Friedman, Ann Richmond, Jessica V. Kaczmarek, Sheau-Chiann Chen, Craig W. Lindsley, Carley M. Bogan, Jennifer B Nadelmann, Jasmine H. Francis, Terry Hsieh, Marion W. Calcutt, David H. Abramson, Albert Liao, Thomas M. Bridges, Anthony B. Daniels |
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| Rok vydání: | 2021 |
| Předmět: |
Melphalan
medicine.medical_specialty endocrine system diseases Retinal Neoplasms medicine.medical_treatment efficacy Pharmacology 03 medical and health sciences Cellular and Molecular Neuroscience Neoplasm Seeding topotecan 0302 clinical medicine Pharmacokinetics medicine Animals Humans Antineoplastic Agents Alkylating Saline Retrospective Studies intravitreal chemotherapy medicine.diagnostic_test business.industry Retinoblastoma toxicity animal models Sensory Systems Vitreous Body Laboratory Science Ophthalmology 030220 oncology & carcinogenesis Intravitreal Injections Toxicity 030221 ophthalmology & optometry vitreous seeds Topotecan Histopathology Rabbits business pharmacokinetics Erg medicine.drug Electroretinography |
| Zdroj: | The British Journal of Ophthalmology |
| ISSN: | 1468-2079 0007-1161 |
| Popis: | BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (pConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective. |
| Databáze: | OpenAIRE |
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