Renal cell carcinoma may adapt to and overcome anti‐angiogenic intervention with thalidomide

• Published in: BJU international Vol. 89; no. 6; pp. 591 - 595
• Main Authors: Douglas, M.L., Reid, J.L., Hii, S.I., Jonsson, J.R., Nicol, D.L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.04.2002; Blackwell
• Subjects: Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic agents; antitumour assays; Biological and medical sciences; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - drug therapy; Cell Division; Chemotherapy; Drug Resistance, Neoplasm; fibroblast growth factor; Humans; integrins; Kidney Neoplasms - blood supply; Kidney Neoplasms - drug therapy; Male; Medical sciences; Mice; Mice, SCID; Neoplasm Transplantation; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; Thalidomide - therapeutic use; Transplantation, Heterologous; Tumor Cells, Cultured; tumour necrosis factor; xenograft model; Antineoplastic agent; Kidney disease; Human; Cell culture; Urinary system disease; Carcinoma; Malignant tumor; Angiogenesis; Chemotherapy; Treatment; Grawitz tumor; Antagonist; Thalidomide
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1046/j.1464-410X.2002.02666.x

Objective To report on the failure of thalidomide to inhibit tumour growth in an animal model of human renal cell carcinoma (RCC). Materials and methods An orthotopic xenograft model of human RCC was used in which tumour cells were implanted in the left kidney of male ‘severe combined immunodeficient’ mice. Thalidomide was administered by intraperitoneal injection and after 34 days the mice were killed. The extent of tumour growth was compared in treated and untreated mice. Total RNA was extracted from both tumour‐affected and contralateral kidneys, and analysed by reverse transcription‐polymerase chain reaction for various genes implicated in angiogenesis and metastasis in RCC. Results Thalidomide failed to inhibit the growth of xenograft tumours. The expression of angiogenic genes, e.g. vascular endothelial growth factor and fibroblast growth factor type 2 (FGF‐2) within normal and tumour‐affected kidney tissue was not reduced by thalidomide. Intratumoral transcription of β3‐integrin, a critical component of angiogenesis, was significantly increased in response to thalidomide treatment (P < 0.01). There was also a trend to increased expression of FGF‐2 and tumour necrosis factor‐α in thalidomide‐treated tumours. Conclusions These findings suggest that RCC is capable of adapting to the inhibitory effects of thalidomide. The current uncertainty surrounding the action of thalidomide in vivo warrants caution about its use in humans. Further studies of thalidomide should be carried out in animal models, particularly to establish its safety and effectiveness as part of a combined therapeutic strategy.