Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model.

Abstract

PURPOSE:

Active and less toxic vitamin D analogs could be useful for clinical applications. In the present study, we evaluated the toxicity and antitumor effect of two new synthetic analogs of vitamin D, namely PRI-1906 [(24E)-24a-Homo-(1S)-1,25-dihydroxyergocalciferol] and its side-chain unsaturated homo analog PRI-1907.

METHODS:

The toxicity and calcemic activity, as well as antitumor effect of calcitriol analogs was investigated in vivo. The studies were performed in a mouse mammary 16/C cancer model. Since calcitriol and its analogs inhibited 16/C tumor growth only slightly, we applied them in the combined therapy with cyclophosphamide (CY). Moreover, cell cycle analysis and VDR and p27 expression were investigated.

RESULTS:

The LD50 values after five daily subcutaneous (s.c.) injections were 7.8, 10.0 and 2.4 microg/kg per day for calcitriol, PRI-1906 and PRI-1907, respectively. The serum calcium level increased to 40, 23 and 63% over the control for these compounds. We also compare the antitumor activity of the PRI-1906 with the calcitriol and previously studied PRI-2191 (1,24-dihydroxyvitamin D3, tacalcitol). Statistically significant inhibition of tumor growth by calcitriol up to the eighth day was observed in all schedules applied. PRI-1906 inhibited the tumor growth at doses 1 and 5 microg/kg per day, and PRI-2191 only at the dose 5 microg/kg per day.

CONCLUSION:

Addition of vitamin D analogs increased the antitumor effect of CY. PRI-1906 exhibited toxicity higher than PRI-2191 but lower than calcitriol and antitumor activity similar to both PRI-2191 and calcitriol. This new analog seems to be a good candidate for the combined treatment of mammary cancer.

• Authors: Joanna Wietrzyk, Dmitry Nevozhay, Magdalena Milczarek, Beata Filip, Andrzej Kutner
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 5 Pg. 787-97 (Oct 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 18188568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 24a-homo-1,15-dihydroxyergocalciferol
• Antineoplastic Agents, Alkylating
• Dihydroxycholecalciferols
• Ergocalciferols
• Vitamins
• 1,25-dihydroxyergocalciferol
• 1 alpha,24-dihydroxyvitamin D3
• Cyclophosphamide
• Calcitriol
• Calcium

Topics

• Animals
• Antineoplastic Agents, Alkylating (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use, toxicity)
• Body Weight
• Calcitriol (blood)
• Calcium (blood)
• Cell Cycle (drug effects)
• Cyclophosphamide (administration & dosage)
• Dihydroxycholecalciferols (administration & dosage)
• Ergocalciferols (administration & dosage)
• Female
• Lethal Dose 50
• Male
• Mammary Neoplasms, Animal (drug therapy)
• Mice
• Mice, Inbred C3H
• Mice, Inbred DBA
• Vitamins (blood)