Interleukin-2, renal cancer

Yang, J.C. et al., Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer, J Clin Oncol, 21, 3127, 2003. 

Bukowski, R.M., Natural history and therapy of metastatic renal cell carcinoma the role of interleukin-2. Cancer, 1997. 80(7) 1198-220. 

Interleukin-2 (IL-2) is an endogenous cytokine that normally exerts a number of beneficial immunologic responses. In particular, IL-2 stimulates the growth and differentiation of T-cell lymphocytes that are selectively toxic for tumor cells.11,33 Hence, recombinant DNA techniques are now used to synthesize IL-2 so that this agent can be used to treat cancers such as renal cancer and malignant melanoma (see... 

Rosenberg SA. Interleukin 2 for patients with renal cancer. Nature Clinical Practice Oncology 2007 4 497. 

In a preclinical study in rats, semapimod suppressed the induction of cytokine storm by the anticancer cytokine interleukin-2 without reducing its anticancer properties, which allowed larger doses of interleukin-2 to be used [118 ]. However, a subsequent phase I trial in 24 patients with melanomas and renal cancers failed to show an increase in the tolerated dose of interleukin-2. In combination with high-dose interleukin-2, semapimod >25 mg/rn seemed to exacerbate interleukin-2-induced nephrotoxicity, as grade 3-4 rises in creatinine developed in three of six patients at dosages of 25 or 32 mg/m, compared with one of 16 patients at doses under 16 mg/rr. The maximum... 

Interleukin-2 has been substituted for mitomycin C in an attempt to decrease myelosuppression, a side effect of mitomycin C. Interferon-a has a direct antiprohfera-tive effect (antiangiogenic) on renal tumor cells in vitro. The co-administration of glucocorticoids improves the tolerance of intermittent high-dose interferon-a (up to 40 million lU/mVday). This study was performed at MDACC on 30 patients with metastatic renal cancer in whom the primary renal lesion was previously resected or embolized (Amato et al. 1995). 

The cytokine interleukin 2 (IL-2) is necessary for T cell growth, proliferation, and differentiation. An FDA-approved recombinant human IL-2 is used clinically as Proleukin (Prometheus Laboratories) for the treatment of metastatic melanoma and renal cell carcinoma. Erythema during IL-2 immunotherapy is common and was well described in a French study nearly 20 years ago with a report on generalized erythema followed by desquamation in 12 patients treated with the cytokine for renal cancer. Urticaria in eight renal cell cancer patients after the end of IL-2 therapy has also been reported. Skin tests with IL-2 on... 

Sleijfer, D.T. et al., Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis, J. Clin. Oncol., 10, 1119, 1992. 

Aldesleukin is a recombinant form of human Interleukin-2 (IL-2). It has been approved for the treatment of malignant melanoma and renal cell cancer. The medicine is administered every 8 hours by a 15-minute intravenous infusion for a maximum of 14 doses. Adverse reactions include hypo- and hypertension, gastrointestinal disturbances, fever, fatigue, lethargy, joint pain, headache. Cardiovascular problems may occur. 

D.R. Parkinson, C.A. Seipp, J.H. Ein-horn, and D.E. White. 1994. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271 907-913. 

Sosman JA, Kohler PC, Hank J, Moore KH, Bechhofer R, Storer B et al. Repetitive weekly cycles of recombinant human interleukin-2 Responses of renal carcinoma with acceptable toxicity. J Natl Cancer Inst 1988 80 60-3... 

Motzer RJ, Rakhit A, Schwartz LH, Olencki T, Malone TM, Sandstrom K et al. Phase 1 trial of subcutaneous human interleukin-12 in patients with advanced renal cell carcinoma. Clin Cancer Res 1998 4 1183-91. 

Three interleukins (ILs) are in use for renal cell carcinoma and malignant melanoma (IL-2), cutaneous T-cell lymphoma (denileukin), and thrombocytopenia associated with cancer chemotherapy (IL-11). These interleukins are protein products that can cause substantial multiorgan toxicity, especially cardiovascular, and limit their full clinical usefulness, which characterizes most interleukins. Denileukin is a fusion protein of IL-2 and diphtheria toxin (Table 9). 

Law TM, Motzer RJ, Mazumdar M, Sell KW, Walther PJ, O Connell M, Khan A, Vlamis V, Vogelzang NJ, Bajorin DF. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995 76(5) 824-32. 

Schomburg A, Kirchner H, Atzpodien J. Renal, metabolic, and hemodynamic side-effects of interleukin-2 and/or interferon alpha evidence of a risk/benefit advantage of subcutaneous therapy. J Cancer Res Clin Oncol 1993 119(12) 745-55. 

White RL Jr, Schwartzentruber DJ, Guleria A, MacFarlane MP, White DE, Tucker E, Rosenberg SA. Cardiopulmonary toxicity of treatment with high dose interleukin-2 in 199 consecutive patients with metastatic melanoma or renal cell carcinoma. Cancer 1994 74(12) 3212-22. 

MacFarlane MP, Yang JC, Guleria AS, White RL Jr, Seipp CA, Einhorn JH, White DE, Rosenberg SA. The hematologic toxicity of interleukin-2 in patients with metastatic melanoma and renal cell carcinoma. Cancer 1995 75(4) 1030-7. 

Webb DE, Austin HA 3rd, Belldegrun A, Vaughan E, Linehan WM, Rosenberg SA. Metabolic and renal effects of interleukin-2 immunotherapy for metastatic cancer. Clin Nephrol 1988 30(3) 141-5. 

Vlasveld LT, van de Wiel-van Kemenade E, de Boer AJ, Sein JJ, Gallee MP, Krediet RT, Mellief CJ, Rankin EM, Hekman A, Figdor CG. Possible role for cytotoxic lymphocytes in the pathogenesis of acute interstitial nephritis after recombinant interleukin-2 treatment for renal cell cancer. Cancer Immunol Immunother 1993 36(3) 210-13. 

Fraenkel PG, Rutkove SB, Matheson JK, Fowkes M, Cannon ME, Patti ME, Atkins MB, Gollob JA. Induction of myasthenia gravis, myositis, and insulin-dependent diabetes mellitus by high-dose interleukin-2 in a patient with renal cell cancer. J Immunother 2002 25(4) 373-8. 

Bortolussi R, Fabiani F, Savron F, Testa V, Lazzarini R, Sorio R, De Conno F, Caraceni A. Acute morphine intoxication during high-dose recombinant interleukin-2 treatment for metastatic renal cell cancer. Eur J Cancer 1994 30A(12) 1905-7. 

Parry-Jones N, Gore ME, Taylor J, Treleaven JG. Delayed haemolytic transfusion reaction caused by anti-M antibody in a patient receiving interleukin-2 and interferon for metastatic renal cell cancer. Chn Lab Haematol 1999 21(6) 407-8. 

Single cases of agranulocytosis and Coombs negative hemolytic anemia have been attributed to twice-weekly mterleukin-12 in 28 patients with renal cell cancer or melanoma (2). The patients responded only to cyclophosphamide and/or glucocorticoids, and the causative role of interleukin-12 was therefore inconclusive. 

Gollob JA, Veeustra KG, Mier JW, Atkius MB. Agranulocytosis aud hemolytic auemia iu patieuts with renal cell cancer treated with interleukin-12. J Immunother 2001 24(l) 91-8. 

Since interleukin-2 induced rate of response in patients with metastatic melanoma or renal cell cancer is schedule and dose dependent, and because renal toxicity is the main cause of treatment discontinuation, more studies are warranted to elucidate the observed nephrotoxicity. 

MarroquinCE, White DE, Steinberg SM, Rosenberg SA, SchwartzentruberDJ Decreased tolerance to interleukin-2 with repeated courses of therapy in patients with metastatic melanoma or renal cell cancer, J Immunother (1997) 2000,23 387-392 Kozeny GA, Nicolas JD, Creekmore S, Sticklin L, Flano JE, Fisher Rl Effects of interleukin-2 immunotherapy on renal function, J Clin Oncol 1988,6 1170-1176... 

Dutcher JP, Fisher Rl, Weiss G, Aronson F, Margolin K, Louie A, Mier J, Caliendo G, Sosman JA, Eckardt JR, Ernest ML, Doroshow J, Atkins M Outpatient subcutaneous interleukin-2 and interferon-alpha for metastatic renal cell cancer five-year follow-up of the Cytokine Working Group Study, Cancer J Sci Am 1997, 3 157-162... 

Schomburg A, Kirchner H, Atzpodien J Renal, metabolic, and hemodynamic side-effects of interleukin-2 and/or interferon alpha evidence of a risk/benefit advantage of subcutaneous therapy, J Cancer Res Clin Oncol 1993,119 745-755 Margolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher Rl, Weiss GR, Doroshow JH, Jaffe HS, Roper M, et al. Inter-leukin-2 and lymphokine-activated killer cell therapy of solid tumors analysis of toxicity and management guidelines, J Clin Oncol 1989,7 486-498... 

Memoli B, De Nicola L, Libetta C, Scialo A, Pacchiano G, Romano P, Palmieri G, Morabito A, Lauria R, Conte G, et al. lnterleukin-2-induced renal dysfunction in cancer patients is reversed by low-dose dopamine infusion, Am J Kidney Dis 1995, 26 27-33 Palmieri G, Morabito A, Lauria R, Montesarchio V, Matano E, Memoli B, Libetta C, Rea A, Merola C, Correale P, et al. Low-dose dopamine induces early recovery of recombinant interleukin-2-impaired renal function, EurJ Cancer 1993,29A 1119-1122... 

SuUivan CM, Smith DM, Matsui NM, et al. Identification of constitutive and gamma-interferon- and interleukin 4-regulated proteins in the human renal carcinoma ceE line ACHN. Cancer Res 1997 57 1137-43. 

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