April 19, 2003
Vitamin D analogs, a new treatment for retinoblastoma
Ophthalmic Genetics 2002, Vol.23, No.3, pp. 137-156
We identified vitamin D receptors in retinoblastoma and examined the effectiveness and mechanism of action of these analogs. Methods: Reverse-transcriptase polymerase chain reaction (RT-PCR) amplification was used to detect vitamin D receptor mRNAs in human and mouse retinoblastomas. The effectiveness and toxicity of vitamin D2, calcitriol, and synthetic analogs were studied in the athymic/Y-79 xenograft and transgenic mouse models of RB. Dosing was 5X/week for five weeks. Dose-response studies focused on tumor inhibition; toxicity studies investigated survival and serum calcium. The mechanism of action of vitamin D was investigated using terminal transferase dUTP labeling 3'-overhang ligation to measure apoptosis; immunohistochemistry measured p53-dependent gene expression and cell proliferation. Result: Vitamin D receptor mRNAs were detectable in Y-79 RB cells, LHß-Tag tumors, and human RB specimens using RT-PCR. Calcitriol inhibited cell growth in vitro. Calcitriol and vitamin D2 inhibited in vivo growth in xenograft and transgenic models, but therapeutic levels were toxic due to hypercalcemia. Two analogs, 16,23-D3 and 1a-OH-D2, inhibited tumors in animal models of RB with reduced toxicity. The mechanism of action appears related to increased p53-related gene expression resulting in increased apoptosis. Conclusion: 16,23-D3 and 1a-OH-D2 are effective in tumor reduction in two mouse models of RB with low toxicity. These results warrant initiating phase 1 and phase 2 clinical studies in children.
Posted by mmiraftab at April 19, 2003 06:16 PM