Toxic effects of melphalan, topotecan and carboplatin on retinal pigment epithelial cells

Abstract

ABSTRACT.Purpose: Clinical evidence of retinal pigment epithelium (RPE) alterations after intra-arterial (IAC) and intravitreal chemotherapy (IViC) of retinoblastoma has been reported. We, therefore, investigated the cellular toxic effects of melphalan, topotecan and carboplatin on the RPE in a cell culture model. Methods: The effects of melphalan, carboplatin and topotecan on ARPE19 cell morphology were examined by phase contrast microscopy. Cell proliferation was quantified by BrdU incorporation, cell viability studied via MTS assays, and cell densities were estimated by Crystal Violet staining, and apoptosis induction studied via caspase 3/7-activity assays after a 24-hr incubation period. Staurosporine, media without fetal bovine serum, diluents of melphalan, carboplatin and topotecan were applied as positive and negative controls, respectively. Results: We observed a concentration-dependent increase in the number and size of gaps in the ARPE19 cell layer with each drug. There was a significant decrease in proliferative activity and cell viability of RPE cells as well as an increase in apoptosis after 24 hrs culture in media supplemented with melphalan and topotecan. Carboplatin had comparable effects on cell proliferation and cell viability; however, no significant apoptotic impacts were observed. The three cytostatic drugs had insignificant effects on cell density measurements. Conclusions: Morphological monitoring and toxicity assays indicate a direct toxic effect of melphalan and the other two cytostatic drugs on ARPE19 cells. Thus, a direct toxic effect of melphalan in vivo after IAC or IViC on the RPE seems probable and may explain the clinical and angiographic RPE alterations observed in some retinoblastoma patients.

Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma

“…Francis et al showed in another study that carboplatin led to slight changes in electroretinogram after injection through the ophthalmic artery compared to melphalan and topotecan . Moreover carboplatin was also the least toxic drug in vitro on retinal pigmentary epithelium cells . According to these promising results, it might be interesting to evaluate IVT of carboplatin in clinical practice as a first‐line treatment to cure retinal tumours (in order to avoid systemic toxicity or intra‐arterial administration).…”

Atypical Retinal Pigment Epithelial Hyperplasia and Glial Proliferation Masquerading as Progressive Recurrent Retinoblastoma: A Case Report Review and Clinicopathologic Correlation

“…Although RPE hyperplasia, hypertrophy, and proliferation following laser therapy and chemotherapy in retinoblastoma patients have been documented, this case report demonstrates that, associated with glial proliferation, RPE hyperplasia can present as a progressive opaque white growth, thus mimicking the clinical presentation of active retinoblastoma, both on clinical exam and OCT imaging [3,4,5,6]. The knowledge of the phenomenon is especially important in patients with increasing retinal whitening after having received multiple rounds of laser consolidation therapy, which is known to induce RPE and glial proliferation.…”

“…It can occur as a result of RPE toxicity from intra-arterial and/or intravitreal chemotherapy, as well as from local laser therapy [3,4,5,6]. Indeed, laser photocoagulation, a common method used for the consolidative treatment of retinoblastoma, has been proven to induce RPE hyperplasia in and around the laser site on the retina using a mouse model [7,8].…”

“…Indeed, laser photocoagulation, a common method used for the consolidative treatment of retinoblastoma, has been proven to induce RPE hyperplasia in and around the laser site on the retina using a mouse model [7,8]. However, most pigmentation patterns of RPE hyperplasia and/or hypertrophy are in contrast to retinoblastoma [3]; RPE changes often appear flat and darkly pigmented, occasionally presenting with a subretinal cleft, and do not tend to show significant or rapid growth, thus differentiating RPE hyperplasia from intraocular tumors [9]. Rarely, however, RPE hyperplasia may mimic an intraocular tumor [3,10].…”

“…However, most pigmentation patterns of RPE hyperplasia and/or hypertrophy are in contrast to retinoblastoma [3]; RPE changes often appear flat and darkly pigmented, occasionally presenting with a subretinal cleft, and do not tend to show significant or rapid growth, thus differentiating RPE hyperplasia from intraocular tumors [9]. Rarely, however, RPE hyperplasia may mimic an intraocular tumor [3,10]. Herein, we present an unusual case of atypical RPE hyperplasia occurring during aggressive laser treatment for a recalcitrant retinoblastoma scar recurrence.…”