Effectiveness of 1alpha-hydroxyvitamin D2 in inhibiting tumor growth in a murine transgenic pigmented ocular tumor model.
OBJECTIVE
To study the effectiveness of the vitamin D analogue 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) in inhibiting ocular tumor growth in transgenic "Tyr-Tag" mice that developed pigmented ocular tumors produced with the simian virus 40 T and t antigens under the control of the mouse tyrosinase gene. These animals develop pigmented intraocular tumors primarily from the retinal pigment epithelium that closely resemble the histologic features and growth pattern of human choroidal melanoma.


METHODS
A total of 73 Tyr-Tag transgenic mice between 6 and 7 weeks old were randomly assigned by sex and litter to 3 treatment groups to receive 0.05 microg/d, 0.1 microg/d, or 0.2 microg/d of 1alpha-OH-D(2); a control group received vehicle (coconut oil). The drug was administered by oral gavage 5 times a week for 5 weeks. The animals were then euthanized and their eyes were enucleated and processed histologically. Three serial sections from each eye were examined microscopically and the mean tumor area measured using Optimus software version 6.5 (Media Cybernetics LP, Silver Spring, Md). Toxic adverse effects were assessed on the basis of mortality, weight loss, and serum calcium levels.


RESULTS
The mean tumor size in the 0.1- microg/d and 0.2- microg/d dose groups was smaller than in the controls (P<.001). No significant difference was seen between the 0.05- microg/d dose group and the control group (P =.64). Survival for the 0.1- microg/d and 0.2- microg/d dose groups was lower than for the controls (95% in the controls vs 85.7% and 73.7%, respectively; P<.01).


CONCLUSIONS
In the Tyr-Tag transgenic mouse, 1alpha-OH-D(2) inhibits pigmented ocular tumor growth at moderate drug levels with relatively low mortality. Clinical Relevance Vitamin D analogues merit further preclinical study in the treatment of ocular melanoma.
Albert
Daniel M
DM
Departments of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, F4/344 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-3284, USA. dalbert@wisc.edu
Kumar
Amit
A
Strugnell
Stephen A
SA
Darjatmoko
Soesiawati R
SR
Lokken
Janice M
JM
Lindstrom
Mary J
MJ
Damico
Christine M
CM
Patel
Sarit
S
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D001835:Body Weight; D002118:Calcium / Q000097:blood; D002830:Choroid Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D004872:Ergocalciferols / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015996:Survival Rate
D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D004872:Ergocalciferols; C042533:1 alpha-hydroxyergocalciferol; D002118:Calcium