Use of Pamidronate and Supplemental Saline to Reduce Toxicity and Increase Effectiveness of Calcitriol in a Retinoblastoma Model

Abstract

Purpose: : 1. To evaluate the efficacy and toxicity of therapy with calcitriol and pamidronate in athymic mice with subcutaneous Y–79 human retinoblastoma tumors. Pamidronate is a nitrogenous bisphosphonate which acts through the HMG CoA–reductase pathway and potentiates osteoclast–induced apoptosis. 2. To reduce toxic effects of calcitriol by using supplemental saline injection based on its use in treating acute hypercalcemia in humans.

Methods: : 42 athymic mice were subcutaneously injected with 5 x 10⁶ human Y79 retinoblastoma cells. Animals were randomized into four groups: group 1 – 0.1 ml vehicle and 0.25 ml saline (negative control); group 2 – 0.05µg of calcitriol in 0.1 ml of vehicle and 0.25 ml saline; group 3 – 0.05µg of calcitriol in 0.1 ml of vehicle and 180µg of pamidronate in 0.25 ml of saline; group 4 – 0.05µg of calcitriol in 0.1 ml of vehicle without saline (positive control). The calcitriol and vehicle were administered intraperitoneally whereas the pamidronate and saline were injected subcutaneously 5 times a week for 4 weeks. Tumor size and body weights were recorded 2 times a week.

Results: : The mean change in tumor volume was as follows: For calcitriol treated animals (group 2) 658.23 mm^{3 ₍}p=0.0056); for combination therapy of calcitriol and pamidronate (group 3) 364 mm³ (p=0.0003). Both were significantly less than the mean change in tumor volume of 1371.78 mm³ in the negative controls (group 1). There was an average weight loss of 0.07 g in group 3 as compared to average weight gains of 3.72 g in group 2 (p=0.0005) and 3.77 g in group 1 (p=0.0003). Moreover the average weight gain and absence of mortality in group 2 receiving calcitriol and saline was highly significant (p=0.0001) as compared to the positive control receiving calcitriol with no saline (group 4). This latter group showed an average weight loss of 4.03 g and 90 % mortality.

Conclusions: : Calcitriol inhibits tumor growth in a Y79 xenograft model in athymic mice and a co–administration of saline significantly reduces the morbidity and mortality. The addition of pamidronate to calcitriol produced further significant reduction of tumor size but increased toxicity.

Keywords: retinoblastoma • oncology • pathobiology