Ability of potent vitamin D3 analogs to inhibit growth of prostate cancer cells in vivo
Vegesna, V.; O'Kelly, J.; Said, J.; Uskokovic, M.; Binderup, L.; Koeffle, H.Phillip.
Anticancer Research 23(1a): 283-289
2003
ISSN/ISBN: 0250-7005 PMID: 12680225 Document Number: 560957
Background: Studies have identified analogues of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), which in vitro are 10- to 3 000-fold more active than 1,25(OH)2D3. We compared in vivo the anti-cancer activity of three potent vitamin D3 analogues and 1,25(OH)2D3 at near to each of their maximal tolerated dose (MTD). Materials and methods: Human LNCaP prostate cancer xenografts were grown in nude mice, and the animals were treated with intraperitoneal injections of either diluant; 1,25(OH)2D3; 1,25-Dihydroxy-20epi-22-oxa-24,26,27-trisho-mocholecalciferol (KH 1060); 1,25-Dihydroxy-22E,24E-diene-24,26,27-trishomocholecalciferol (EB 1039); and 1,25-Dihydroxy-16-ene-24-oxo-19-norcholecalciferol (RO 26-9114). Tumour sizes were measured weekly, and tumour weights were measured at autopsy on the 12th week. Results: Each of the analogues equally and markedly inhibited the growth of prostate cancer xenografts. The 1,25(OH)2D3 initially inhibited growth but, by the time of sacrifice, the tumours were nearly the same size as diluant controls. The histological examination of the tumours showed that the analogues produced tumour necrosis and microcalcification. None of the mice developed hypercalcaemia, which is the major toxicity of vitamin D3 compounds. Conclusion: The MTD of the analogues varied by 400-fold, but each had similar efficacy suggesting that, when choosing a vitamin D analogue for clinical study, overall efficacy without toxicity is more important than the total amount of the compound that can be administered. In summary, we have identified three vitamin D analogues that show marked potency in vivo to inhibit growth of human prostate cancer xenografts; each had no detectable toxicity. This study should help lay the foundation for clinical studies.