Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience

Kahan, Barry D.; Knight, Richard J.; Schoenberg, L.; Pobielski, J.; Kerman, Ronald H.; Mahalati, Kamran; Yakupoğlu, Yarkın Kamil; Aki, Fazıl Tuncay; Katz, Stephen M.; Buren, Charles T. Van

doi:10.1016/s0041-1345(03)00351-8

Cited by 80 publications

(44 citation statements)

References 23 publications

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“…62 In addition, sirolimus appears to be associated with a lower risk of developing and successful treatment of post-transplant malignancies including PTLD, skin carcinomas and Karposi's sarcoma. [63][64][65][66][67][68] These results suggest that sirolimus may minimize the risk of developing post-transplant malignancies while maintaining organ transplant viability and may be used to continue immunosuppression and inhibit malignancies recurrence in successfully treated patients.…”

Section: Clinical Activity Of Sirolimus and Derivativesmentioning

confidence: 92%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

183

134

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The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

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Section: Clinical Activity Of Sirolimus and Derivativesmentioning

confidence: 92%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

183

134

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“…Rapamycin-based regimens have been reported to provide effective rejection prophylaxis without the risks of hypertension and decline in renal function associated with calcineurin inhibitors [2]. Most interestingly, rapamycin treatment in combination with other immunosuppressants has been reported to improve renal function [3,4] and to decrease the elevated risk of developing cancer in renal transplanted patients [5].…”

Section: Introductionmentioning

confidence: 99%

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

et al. 2007

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Rapamycin is a potent immunosuppressant with antitumoral properties widely used in the field of renal transplantation. To test the hypothesis that the antiproliferative and antiangiogenic activity of rapamycin interferes with the normal structure and function of growth plate and impairs longitudinal growth, 4-week-old male rats (n=10/ group) receiving 2 mg/kg per day of intraperitoneal rapamycin (RAPA) or vehicle (C) for 14 days were compared. Rapamycin markedly decreased bone longitudinal growth rate (94±3 vs. 182±3 μm/day), body weight gain (60.2±1.4 vs. 113.6±1.9 g), food intake (227.8±2.6 vs. 287.5±3.4 g), and food efficiency (0.26±0.00 vs. 0.40± 0.01 g/g). Signs of altered cartilage formation such as reduced chondrocyte proliferation (bromodeoxiuridine-labeled cells 32.9±1.4 vs. 45.2±1.1%), disturbed maturation and hypertrophy (height of terminal chondrocytes 26±0 vs. 29±0 μm), and decreased cartilage resorption (18.7±0.5 vs. 31.0±0.8 tartrate-resistant phosphatase alkaline reactive cells per 100 terminal chondrocytes), together with morphological evidence of altered vascular invasion, were seen in the growth plate of RAPA animals. This study indicates that rapamycin can severely impair body growth in fastgrowing rats and distort growth-plate structure and dynamics. These undesirable effects must be kept in mind when rapamycin is administered to children.

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“…24 Estudo realizado em centro único mostrou uma taxa de interrupção do uso de SRL de apenas 13% após 10 anos de seguimento. 7 Em comparação, fármacos contento ácido micofenólico apresentam taxas de interrupção de uso por intolerância que variam de 2% a 13% entre o primeiro e o terceiro anos após o transplante. 32 Receptores cujo esquema imunossupressor inicial consiste em ácido micofenó-lico combinado a CSA ou TAC permaneceram com o mesmo tratamento em 63,5% e 70,9% dos casos, respectivamente, após 3 anos de transplante.…”

Section: Discussionunclassified

“…36 Entretanto, a magnitude do aumento nas concentrações médias de colesterol e triglicérides foi pequena, apesar de maior entre os pacientes recebendo CSA, com tendência à redução após o primeiro ano do transplante. 7,16 Finalmente, apesar da possibilidade de interferência do SRL sobre o metabolismo de carboidratos, a concentração média de glicose ficou dentro dos limites de normalidade, não se observando diferença entre os pacientes que receberam CSA ou TAC. Entretanto, a análise da incidência de diabetes mellitus após o transplante renal não foi um dos objetivos desse estudo.…”

Section: Discussionunclassified