Effectiveness of 1α-Hydroxyvitamin D2 in InhibitingTumor Growth in a Murine Transgenic Pigmented Ocular Tumor Model

Abstract

To study the effectiveness of the vitamin D analogue 1␣-hydroxyvitamin D 2 (1␣-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 µg/d, 0.1 µg/d, or 0.2 µg/d of 1␣-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-µg/d and 0.2µg/d dose groups was smaller than in the controls (PϽ.001). No significant difference was seen between the 0.05-µg/d dose group and the control group (P=.64). Survival for the 0.1-µg/d and 0.2-µg/d dose groups was lower than for the controls (95% in the controls vs 85.7% and 73.7%, respectively; PϽ.01). Conclusion:In the Tyr-Tag transgenic mouse, 1␣-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.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…1,25(OH) 2 D3 at pharmacological doses inhibited growth of VDR positive human melanoma xenografts in vivo, while being well tolerated when a low calcium diet was used [ 603 ]. In the Tyr-Tag transgenic mouse, 1α(OH)D2 inhibited pigmented ocular tumor growth at moderate drug levels with relatively low mortality [ 604 ]. In fact, the total body score was higher in the treatment group compared to control group (2.8 vs. 2.55).…”

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…1,25(OH) 2 D3 at pharmacological doses inhibited growth of VDR positive human melanoma xenografts in vivo, while being well tolerated when a low calcium diet was used [ 603 ]. In the Tyr-Tag transgenic mouse, 1α(OH)D2 inhibited pigmented ocular tumor growth at moderate drug levels with relatively low mortality [ 604 ]. In fact, the total body score was higher in the treatment group compared to control group (2.8 vs. 2.55).…”

Association Between Simian Virus 40 and Human Tumors

“…Exploiting the vast SV40 oncogenicity in vivo , SV40 transgenic animals provided good models for studying tumor initiation/progression and innovative anti-cancer therapies (146). Transgenic animals develop ependymomas, choroid plexus papillomas (147), hepatocellular carcinomas (139, 144), brain (148), bladder (140), and bowel tumors (149), as well as eye tumors, including ocular and/or lens tumors (150). The multistage progression of prostate carcinoma has also been largely studied employing SV40-transgenic mice (128–130, 132, 134–136, 151, 152).…”

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

“…256 Also, Albert and coworkers found that 1(OH)D2 effectively decreased growth of pigmented ocular tumor in the Tyr-Tag transgenic mouse. 264 …”

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…1,25(OH) 2 D3 at pharmacological doses inhibited growth of VDR positive human melanoma xenografts in vivo, while being well tolerated when a low calcium diet was used [ 603 ]. In the Tyr-Tag transgenic mouse, 1α(OH)D2 inhibited pigmented ocular tumor growth at moderate drug levels with relatively low mortality [ 604 ]. In fact, the total body score was higher in the treatment group compared to control group (2.8 vs. 2.55).…”

Association Between Simian Virus 40 and Human Tumors

“…Exploiting the vast SV40 oncogenicity in vivo , SV40 transgenic animals provided good models for studying tumor initiation/progression and innovative anti-cancer therapies (146). Transgenic animals develop ependymomas, choroid plexus papillomas (147), hepatocellular carcinomas (139, 144), brain (148), bladder (140), and bowel tumors (149), as well as eye tumors, including ocular and/or lens tumors (150). The multistage progression of prostate carcinoma has also been largely studied employing SV40-transgenic mice (128–130, 132, 134–136, 151, 152).…”

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

“…256 Also, Albert and coworkers found that 1(OH)D2 effectively decreased growth of pigmented ocular tumor in the Tyr-Tag transgenic mouse. 264 …”

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…1,25(OH) 2 D3 at pharmacological doses inhibited growth of VDR positive human melanoma xenografts in vivo, while being well tolerated when a low calcium diet was used [ 603 ]. In the Tyr-Tag transgenic mouse, 1α(OH)D2 inhibited pigmented ocular tumor growth at moderate drug levels with relatively low mortality [ 604 ]. In fact, the total body score was higher in the treatment group compared to control group (2.8 vs. 2.55).…”

Association Between Simian Virus 40 and Human Tumors

“…Exploiting the vast SV40 oncogenicity in vivo , SV40 transgenic animals provided good models for studying tumor initiation/progression and innovative anti-cancer therapies (146). Transgenic animals develop ependymomas, choroid plexus papillomas (147), hepatocellular carcinomas (139, 144), brain (148), bladder (140), and bowel tumors (149), as well as eye tumors, including ocular and/or lens tumors (150). The multistage progression of prostate carcinoma has also been largely studied employing SV40-transgenic mice (128–130, 132, 134–136, 151, 152).…”

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

“…256 Also, Albert and coworkers found that 1(OH)D2 effectively decreased growth of pigmented ocular tumor in the Tyr-Tag transgenic mouse. 264 …”