PHARMACOLOGICAL STRATEGIES TO OVERCOME MELPHALAN RESISTANCE IN VITRO

CANCELA MARÍA BELÉN; WINTER URSULA; ZUGBI SANTIAGO; ASCHERO ROSARIO; SGROI MARIANA; SAMPOR CLAUDIA; FANDIÑO A; LUBINIECKE FABIANA; CHANTADA GUILERMO; CARCABOSO ANGEL; SCHAIQUEVICH PAULA

Mar del plata

Congreso; Reunión Anual de Sociedades de Biociencia; 2019

Sociedad argentina de farmacologia experimental

Fortunately, treatment of Retinoblastoma (Rb) has enhanced significantly over recent years, improving the rate of ocular preservation. Nevertheless, some children experience a relapse, or recurrence, of Rb. Rb relapse may be mediated by acquired pharmacological resistance leading to the need of higher doses of chemotherapy or to switch to other active drugs to respond. Scarce data is available on pharmacological resistance after initial chemotherapeutic treatment in Rb. Thus, our aim was to establish a melphalan-resistant cell subtype and to study the degree of resistance to melphalan, cross-resistance to other drugs commonly used in Rb. We also set out to evaluate melphalan low-dose, continuous, metronomic administration scheme and the cytotoxic effect of a repositioning drug, digoxin.A primary cell culture was established from the tumor biopsy of an upfront enucleated patient with intraocular Rb. The parental cell line (HSJD-RBT-7-PA) was exposed to three weekly doses of melphalan equivalent to the IC50. After drug washout, melphalan, topotecan and carboplatin IC50 was determined in the meplphalan-resistant subtype (HSJD-RBT-7-ML) to verify resistance and to test for possible cross-resistance using the MTT assay. Also metronomic melphalan and digoxin IC50 was determined in the meplphalan-resistant subtype (HSJD-RBT-7-ML) as two possible alternatives to avoid acquired resistance in vitro, using the MTT assay. Mean (range) melphalan IC50 in HSJD-RBT-7-ML was 1,3 µM (0,8-1,4), 4,3-fold higher than melphalan IC50 in HSJD-RBT-7-PA (p