Rapamycin is an effective inhibitor of human renal cancer metastasis

Fu L. Luan, Ruchuang Ding, Vijay K. Sharma, W. James Chon, Milagros Lagman, Manikkam Suthanthiran

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

Background. Human renal cell cancer (RCC) is common and is 10 to 100 times more frequent in patients with end-stage renal disease (ESRD) and candidates for renal transplantation. Treatment of metastatic RCC is largely ineffective and is further undermined by immunosuppressive therapy in transplant recipients. A treatment regimen that prevents transplant rejection while constraining RCC progression would be of high value. Methods. We developed a human RCC pulmonary metastasis model using human RCC 786-O as the tumor challenge and the severe combined immunodeficient (SCID) beige mouse as the host. We explored the effect of rapamycin, cyclosporine, or rapamycin plus cyclosporine on the development of pulmonary metastases and survival. The effects of the drugs on tumor cell growth, apoptosis, and expression of vascular endothelial growth factor (VEGF-A) and transforming growth factor β1 (TGF-β1) were also investigated. Results. Rapamycin reduced, whereas cyclosporine increased, the number of pulmonary metastases. Rapamycin was effective in cyclosporine-treated mice, and rapamycin or rapamycin plus cyclosporine prolonged survival. Rapamycin growth arrested RCC 786-O at the G1 phase and reduced VEGF-A expression. Immunostaining of lung tissues for von Willebrand factor was minimal and circulating levels of VEGF-A and TGF-β1 were lower in the rapamycin-treated mice compared to untreated or cyclosporine-treated mice. Conclusion. Our findings support the idea that rapamycin may be of value for patients with RCC and that its antitumor efficacy is realized by cell cycle arrest and targeted reduction of VEGF-A and TGF-β1. A regimen of rapamycin and cyclosporine, demonstrated to be effective in reducing acute rejection of renal allografts, may prevent RCC progression as wel, and has the potential to prevent mortality due to RCC in patients with ESRD who have received renal allografts.

Original languageEnglish
Pages (from-to)917-926
Number of pages10
JournalKidney International
Volume63
Issue number3
DOIs
Publication statusPublished - 1 Mar 2003
Externally publishedYes

Fingerprint

Kidney Neoplasms
Sirolimus
Renal Cell Carcinoma
Neoplasm Metastasis
Cyclosporine
Vascular Endothelial Growth Factor A
Transforming Growth Factors
Lung
Chronic Kidney Failure
Allografts
Kidney
SCID Mice
Survival
Graft Rejection
G1 Phase
von Willebrand Factor
Immunosuppressive Agents
Growth
Cell Cycle Checkpoints
Kidney Transplantation

Keywords

  • Cyclosporine
  • Rapamycin
  • Renal cancer

ASJC Scopus subject areas

  • Nephrology

Cite this

Rapamycin is an effective inhibitor of human renal cancer metastasis. / Luan, Fu L.; Ding, Ruchuang; Sharma, Vijay K.; Chon, W. James; Lagman, Milagros; Suthanthiran, Manikkam.

In: Kidney International, Vol. 63, No. 3, 01.03.2003, p. 917-926.

Research output: Contribution to journalArticle

Luan, Fu L. ; Ding, Ruchuang ; Sharma, Vijay K. ; Chon, W. James ; Lagman, Milagros ; Suthanthiran, Manikkam. / Rapamycin is an effective inhibitor of human renal cancer metastasis. In: Kidney International. 2003 ; Vol. 63, No. 3. pp. 917-926.
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abstract = "Background. Human renal cell cancer (RCC) is common and is 10 to 100 times more frequent in patients with end-stage renal disease (ESRD) and candidates for renal transplantation. Treatment of metastatic RCC is largely ineffective and is further undermined by immunosuppressive therapy in transplant recipients. A treatment regimen that prevents transplant rejection while constraining RCC progression would be of high value. Methods. We developed a human RCC pulmonary metastasis model using human RCC 786-O as the tumor challenge and the severe combined immunodeficient (SCID) beige mouse as the host. We explored the effect of rapamycin, cyclosporine, or rapamycin plus cyclosporine on the development of pulmonary metastases and survival. The effects of the drugs on tumor cell growth, apoptosis, and expression of vascular endothelial growth factor (VEGF-A) and transforming growth factor β1 (TGF-β1) were also investigated. Results. Rapamycin reduced, whereas cyclosporine increased, the number of pulmonary metastases. Rapamycin was effective in cyclosporine-treated mice, and rapamycin or rapamycin plus cyclosporine prolonged survival. Rapamycin growth arrested RCC 786-O at the G1 phase and reduced VEGF-A expression. Immunostaining of lung tissues for von Willebrand factor was minimal and circulating levels of VEGF-A and TGF-β1 were lower in the rapamycin-treated mice compared to untreated or cyclosporine-treated mice. Conclusion. Our findings support the idea that rapamycin may be of value for patients with RCC and that its antitumor efficacy is realized by cell cycle arrest and targeted reduction of VEGF-A and TGF-β1. A regimen of rapamycin and cyclosporine, demonstrated to be effective in reducing acute rejection of renal allografts, may prevent RCC progression as wel, and has the potential to prevent mortality due to RCC in patients with ESRD who have received renal allografts.",
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T1 - Rapamycin is an effective inhibitor of human renal cancer metastasis

AU - Luan, Fu L.

AU - Ding, Ruchuang

AU - Sharma, Vijay K.

AU - Chon, W. James

AU - Lagman, Milagros

AU - Suthanthiran, Manikkam

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N2 - Background. Human renal cell cancer (RCC) is common and is 10 to 100 times more frequent in patients with end-stage renal disease (ESRD) and candidates for renal transplantation. Treatment of metastatic RCC is largely ineffective and is further undermined by immunosuppressive therapy in transplant recipients. A treatment regimen that prevents transplant rejection while constraining RCC progression would be of high value. Methods. We developed a human RCC pulmonary metastasis model using human RCC 786-O as the tumor challenge and the severe combined immunodeficient (SCID) beige mouse as the host. We explored the effect of rapamycin, cyclosporine, or rapamycin plus cyclosporine on the development of pulmonary metastases and survival. The effects of the drugs on tumor cell growth, apoptosis, and expression of vascular endothelial growth factor (VEGF-A) and transforming growth factor β1 (TGF-β1) were also investigated. Results. Rapamycin reduced, whereas cyclosporine increased, the number of pulmonary metastases. Rapamycin was effective in cyclosporine-treated mice, and rapamycin or rapamycin plus cyclosporine prolonged survival. Rapamycin growth arrested RCC 786-O at the G1 phase and reduced VEGF-A expression. Immunostaining of lung tissues for von Willebrand factor was minimal and circulating levels of VEGF-A and TGF-β1 were lower in the rapamycin-treated mice compared to untreated or cyclosporine-treated mice. Conclusion. Our findings support the idea that rapamycin may be of value for patients with RCC and that its antitumor efficacy is realized by cell cycle arrest and targeted reduction of VEGF-A and TGF-β1. A regimen of rapamycin and cyclosporine, demonstrated to be effective in reducing acute rejection of renal allografts, may prevent RCC progression as wel, and has the potential to prevent mortality due to RCC in patients with ESRD who have received renal allografts.

AB - Background. Human renal cell cancer (RCC) is common and is 10 to 100 times more frequent in patients with end-stage renal disease (ESRD) and candidates for renal transplantation. Treatment of metastatic RCC is largely ineffective and is further undermined by immunosuppressive therapy in transplant recipients. A treatment regimen that prevents transplant rejection while constraining RCC progression would be of high value. Methods. We developed a human RCC pulmonary metastasis model using human RCC 786-O as the tumor challenge and the severe combined immunodeficient (SCID) beige mouse as the host. We explored the effect of rapamycin, cyclosporine, or rapamycin plus cyclosporine on the development of pulmonary metastases and survival. The effects of the drugs on tumor cell growth, apoptosis, and expression of vascular endothelial growth factor (VEGF-A) and transforming growth factor β1 (TGF-β1) were also investigated. Results. Rapamycin reduced, whereas cyclosporine increased, the number of pulmonary metastases. Rapamycin was effective in cyclosporine-treated mice, and rapamycin or rapamycin plus cyclosporine prolonged survival. Rapamycin growth arrested RCC 786-O at the G1 phase and reduced VEGF-A expression. Immunostaining of lung tissues for von Willebrand factor was minimal and circulating levels of VEGF-A and TGF-β1 were lower in the rapamycin-treated mice compared to untreated or cyclosporine-treated mice. Conclusion. Our findings support the idea that rapamycin may be of value for patients with RCC and that its antitumor efficacy is realized by cell cycle arrest and targeted reduction of VEGF-A and TGF-β1. A regimen of rapamycin and cyclosporine, demonstrated to be effective in reducing acute rejection of renal allografts, may prevent RCC progression as wel, and has the potential to prevent mortality due to RCC in patients with ESRD who have received renal allografts.

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