TNF- α augments intratumoural concentrations of doxorubicin in TNF- α -based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects (original) (raw)

Abstract

We have shown previously that isolated limb perfusion (ILP) in sarcoma-bearing rats results in high response rates when melphalan is used in combination with tumour necrosis factor alpha (TNF-α). This is in line with observations in patients. Here we show that ILP with doxorubicin in combination with TNF-α has comparable effects in two different rat sarcoma tumour models. The addition of TNF-α exhibits a synergistic anti-tumour effect, resulting in regression of the tumour in 54% and 100% of the cases for the BN175-fibrosarcoma and the ROS-1 osteosarcoma respectively. The combination is shown to be mandatory for optimal tumour response. The effect of high dose TNF-α on the activity of cytotoxic agents in ILP is still unclear. We investigated possible modes by which TNF-α could modulate the activity of doxorubicin. In both tumour models increased accumulation of doxorubicin in tumour tissue was found: 3.1-fold in the BN175 and 1.8-fold in the ROS-1 sarcoma after ILP with doxorubicin combined with TNF-α in comparison with an ILP with doxorubicin alone. This increase in local drug concentration may explain the synergistic anti-tumour responses after ILP with the combination. In vitro TNF-α fails to augment drug uptake in tumour cells or to increase cytotoxicity of the drug. These findings make it unlikely that TNF-α directly modulates the activity of doxorubicin in vivo. As TNF-α by itself has no or only minimal effect on tumour growth, an increase in local concentrations of chemotherapeutic drugs might well be the main mechanism for the synergistic anti-tumour effects. © 2000 Cancer Research Campaign

Keywords: doxorubicin, isolated limb perfusion, rat, sarcoma, tumour necrosis factor-alpha

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Selected References

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  1. Abolhoda A., Brooks A., Nawata S., Kaneda Y., Cheng H., Burt M. E. Isolated lung perfusion with doxorubicin prolongs survival in a rodent model of pulmonary metastases. Ann Thorac Surg. 1997 Jul;64(1):181–184. doi: 10.1016/s0003-4975(97)00450-5. [DOI] [PubMed] [Google Scholar]
  2. Alexander R. B., Nelson W. G., Coffey D. S. Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II. Cancer Res. 1987 May 1;47(9):2403–2406. [PubMed] [Google Scholar]
  3. Asher A., Mulé J. J., Reichert C. M., Shiloni E., Rosenberg S. A. Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo. J Immunol. 1987 Feb 1;138(3):963–974. [PubMed] [Google Scholar]
  4. Benckhuijsen C., Kroon B. B., van Geel A. N., Wieberdink J. Regional perfusion treatment with melphalan for melanoma in a limb: an evaluation of drug kinetics. Eur J Surg Oncol. 1988 Apr;14(2):157–163. [PubMed] [Google Scholar]
  5. Benckhuysen C., Van Dijk W. J., Van't Hoff S. C. High-flow isolation perfusion of the rat hind limb in vivo. J Surg Oncol. 1982 Dec;21(4):249–257. doi: 10.1002/jso.2930210412. [DOI] [PubMed] [Google Scholar]
  6. Bielack S. S., Erttmann R., Kempf-Bielack B., Winkler K. Impact of scheduling on toxicity and clinical efficacy of doxorubicin: what do we know in the mid-nineties? Eur J Cancer. 1996 Sep;32A(10):1652–1660. doi: 10.1016/0959-8049(96)00177-3. [DOI] [PubMed] [Google Scholar]
  7. Bonavida B., Tsuchitani T., Zighelboim J., Berek J. S. Synergy is documented in vitro with low-dose recombinant tumor necrosis factor, cisplatin, and doxorubicin in ovarian cancer cells. Gynecol Oncol. 1990 Sep;38(3):333–339. doi: 10.1016/0090-8258(90)90068-v. [DOI] [PubMed] [Google Scholar]
  8. Budd G. T. Palliative chemotherapy of adult soft tissue sarcomas. Semin Oncol. 1995 Apr;22(2 Suppl 3):30–34. [PubMed] [Google Scholar]
  9. Eggermont A. M., Schraffordt Koops H., Klausner J. M., Kroon B. B., Schlag P. M., Liénard D., van Geel A. N., Hoekstra H. J., Meller I., Nieweg O. E. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg. 1996 Dec;224(6):756–765. doi: 10.1097/00000658-199612000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eggermont A. M., Schraffordt Koops H., Liénard D., Kroon B. B., van Geel A. N., Hoekstra H. J., Lejeune F. J. Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol. 1996 Oct;14(10):2653–2665. doi: 10.1200/JCO.1996.14.10.2653. [DOI] [PubMed] [Google Scholar]
  11. Fajardo L. F., Kwan H. H., Kowalski J., Prionas S. D., Allison A. C. Dual role of tumor necrosis factor-alpha in angiogenesis. Am J Pathol. 1992 Mar;140(3):539–544. [PMC free article] [PubMed] [Google Scholar]
  12. Folli S., Pèlegrin A., Chalandon Y., Yao X., Buchegger F., Lienard D., Lejeune F., Mach J. P. Tumor-necrosis factor can enhance radio-antibody uptake in human colon carcinoma xenografts by increasing vascular permeability. Int J Cancer. 1993 Mar 12;53(5):829–836. doi: 10.1002/ijc.2910530521. [DOI] [PubMed] [Google Scholar]
  13. Fruehauf J. P., Mimnaugh E. G., Sinha B. K. Doxorubicin-induced cross-resistance to tumor necrosis factor (TNF) related to differential TNF processing. J Immunother (1991) 1991 Jun;10(3):165–173. doi: 10.1097/00002371-199106000-00002. [DOI] [PubMed] [Google Scholar]
  14. Klaase J. M., Kroon B. B., Benckhuijsen C., van Geel A. N., Albus-Lutter C. E., Wieberdink J. Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer. 1989 Aug 1;64(3):616–621. doi: 10.1002/1097-0142(19890801)64:3<616::aid-cncr2820640309>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  15. Kristensen C. A., Nozue M., Boucher Y., Jain R. K. Reduction of interstitial fluid pressure after TNF-alpha treatment of three human melanoma xenografts. Br J Cancer. 1996 Aug;74(4):533–536. doi: 10.1038/bjc.1996.397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lee Y. T., Chan K. K., Harris P. A., Cohen J. L. Distribution of adriamycin in cancer patients: tissue uptakes, plasma concentration after IV and hepatic IA administration. Cancer. 1980 May 1;45(9):2231–2239. doi: 10.1002/1097-0142(19800501)45:9<2231::aid-cncr2820450902>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  17. Lejeune F. J., Liénard D., Leyvraz S., Mirimanoff R. O. Regional therapy of melanoma. Eur J Cancer. 1993;29A(4):606–612. doi: 10.1016/s0959-8049(05)80163-7. [DOI] [PubMed] [Google Scholar]
  18. Lienard D., Ewalenko P., Delmotte J. J., Renard N., Lejeune F. J. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol. 1992 Jan;10(1):52–60. doi: 10.1200/JCO.1992.10.1.52. [DOI] [PubMed] [Google Scholar]
  19. Liénard D., Eggermont A. M., Schraffordt Koops H., Kroon B. B., Rosenkaimer F., Autier P., Lejeune F. J. Isolated perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study. Melanoma Res. 1994 Mar;4 (Suppl 1):21–26. [PubMed] [Google Scholar]
  20. Luk C. K., Tannock I. F. Flow cytometric analysis of doxorubicin accumulation in cells from human and rodent cell lines. J Natl Cancer Inst. 1989 Jan 4;81(1):55–59. doi: 10.1093/jnci/81.1.55. [DOI] [PubMed] [Google Scholar]
  21. Manusama E. R., Nooijen P. T., Stavast J., Durante N. M., Marquet R. L., Eggermont A. M. Synergistic antitumour effect of recombinant human tumour necrosis factor alpha with melphalan in isolated limb perfusion in the rat. Br J Surg. 1996 Apr;83(4):551–555. doi: 10.1002/bjs.1800830438. [DOI] [PubMed] [Google Scholar]
  22. Manusama E. R., Nooijen P. T., Stavast J., de Wilt J. H., Marquet R. L., Eggermont A. M. Assessment of the role of neutrophils on the antitumor effect of TNFalpha in an in vivo isolated limb perfusion model in sarcoma-bearing brown Norway rats. J Surg Res. 1998 Aug;78(2):169–175. doi: 10.1006/jsre.1997.5256. [DOI] [PubMed] [Google Scholar]
  23. Manusama E. R., Stavast J., Durante N. M., Marquet R. L., Eggermont A. M. Isolated limb perfusion with TNF alpha and melphalan in a rat osteosarcoma model: a new anti-tumour approach. Eur J Surg Oncol. 1996 Apr;22(2):152–157. doi: 10.1016/s0748-7983(96)90671-x. [DOI] [PubMed] [Google Scholar]
  24. Mayer L. D., Tai L. C., Ko D. S., Masin D., Ginsberg R. S., Cullis P. R., Bally M. B. Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res. 1989 Nov 1;49(21):5922–5930. [PubMed] [Google Scholar]
  25. Mürdter T. E., Sperker B., Kivistö K. T., McClellan M., Fritz P., Friedel G., Linder A., Bosslet K., Toomes H., Dierkesmann R. Enhanced uptake of doxorubicin into bronchial carcinoma: beta-glucuronidase mediates release of doxorubicin from a glucuronide prodrug (HMR 1826) at the tumor site. Cancer Res. 1997 Jun 15;57(12):2440–2445. [PubMed] [Google Scholar]
  26. Nooijen P. T., Manusama E. R., Eggermont A. M., Schalkwijk L., Stavast J., Marquet R. L., de Waal R. M., Ruiter D. J. Synergistic effects of TNF-alpha and melphalan in an isolated limb perfusion model of rat sarcoma: a histopathological, immunohistochemical and electron microscopical study. Br J Cancer. 1996 Dec;74(12):1908–1915. doi: 10.1038/bjc.1996.652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Olieman A. F., van Ginkel R. J., Hoekstra H. J., Mooyaart E. L., Molenaar W. M., Koops H. S. Angiographic response of locally advanced soft-tissue sarcoma following hyperthermic isolated limb perfusion with tumor necrosis factor. Ann Surg Oncol. 1997 Jan;4(1):64–69. doi: 10.1007/BF02316812. [DOI] [PubMed] [Google Scholar]
  28. Prewitt T. W., Matthews W., Chaudhri G., Pogrebniak H. W., Pass H. I. Tumor necrosis factor induces doxorubicin resistance to lung cancer cells in vitro. J Thorac Cardiovasc Surg. 1994 Jan;107(1):43–49. [PubMed] [Google Scholar]
  29. Renard N., Nooijen P. T., Schalkwijk L., De Waal R. M., Eggermont A. M., Liénard D., Kroon B. B., Lejeune F. J., Ruiter D. J. VWF release and platelet aggregation in human melanoma after perfusion with TNF alpha. J Pathol. 1995 Jul;176(3):279–287. doi: 10.1002/path.1711760310. [DOI] [PubMed] [Google Scholar]
  30. Ridge J. A., Collin C., Bading J. R., Hancock C., Conti P. S., Daly J. M., Raaf J. H. Increased adriamycin levels in hepatic implants of rabbit Vx-2 carcinoma from regional infusion. Cancer Res. 1988 Aug 15;48(16):4584–4587. [PubMed] [Google Scholar]
  31. Rossi C. R., Vecchiato A., Da Pian P. P., Nitti D., Lise M., Melanotte P. L., Turra S., Vigliani F. Adriamycin in hyperthermic perfusion for advanced limb sarcomas. Ann Oncol. 1992 Apr;3 (Suppl 2):S111–S113. doi: 10.1093/annonc/3.suppl_2.s111. [DOI] [PubMed] [Google Scholar]
  32. Rüegg C., Yilmaz A., Bieler G., Bamat J., Chaubert P., Lejeune F. J. Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med. 1998 Apr;4(4):408–414. doi: 10.1038/nm0498-408. [DOI] [PubMed] [Google Scholar]
  33. Safrit J. T., Berek J. S., Bonavida B. Sensitivity of drug-resistant human ovarian tumor cell lines to combined effects of tumor necrosis factor (TNF-alpha) and doxorubicin: failure of the combination to modulate the MDR phenotype. Gynecol Oncol. 1993 Feb;48(2):214–220. doi: 10.1006/gyno.1993.1036. [DOI] [PubMed] [Google Scholar]
  34. Sato N., Goto T., Haranaka K., Satomi N., Nariuchi H., Mano-Hirano Y., Sawasaki Y. Actions of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition, and cytotoxicity. J Natl Cancer Inst. 1986 Jun;76(6):1113–1121. [PubMed] [Google Scholar]
  35. Shimomura K., Manda T., Mukumoto S., Kobayashi K., Nakano K., Mori J. Recombinant human tumor necrosis factor-alpha: thrombus formation is a cause of anti-tumor activity. Int J Cancer. 1988 Feb 15;41(2):243–247. doi: 10.1002/ijc.2910410215. [DOI] [PubMed] [Google Scholar]
  36. Smyth M. J., Pietersz G. A., McKenzie I. F. Increased antitumor effect of immunoconjugates and tumor necrosis factor in vivo. Cancer Res. 1988 Jul 1;48(13):3607–3612. [PubMed] [Google Scholar]
  37. Soranzo C., Perego P., Zunino F. Effect of tumor necrosis factor on human tumor cell lines sensitive and resistant to cytotoxic drugs, and its interaction with chemotherapeutic agents. Anticancer Drugs. 1990 Dec;1(2):157–163. doi: 10.1097/00001813-199012000-00007. [DOI] [PubMed] [Google Scholar]
  38. Suzuki S., Ohta S., Takashio K., Nitanai H., Hashimoto Y. Augmentation for intratumoral accumulation and anti-tumor activity of liposome-encapsulated adriamycin by tumor necrosis factor-alpha in mice. Int J Cancer. 1990 Dec 15;46(6):1095–1100. doi: 10.1002/ijc.2910460624. [DOI] [PubMed] [Google Scholar]
  39. Tonak J., Hermanek P., Banz H., Groitl H. Cytotoxics and hyperthermic perfusion: a preliminary study. Cancer Treat Rev. 1979 Jun;6 (Suppl):135–141. doi: 10.1016/s0305-7372(79)80033-x. [DOI] [PubMed] [Google Scholar]
  40. Watanabe N., Niitsu Y., Umeno H., Kuriyama H., Neda H., Yamauchi N., Maeda M., Urushizaki I. Toxic effect of tumor necrosis factor on tumor vasculature in mice. Cancer Res. 1988 Apr 15;48(8):2179–2183. [PubMed] [Google Scholar]
  41. Weksler B., Lenert J., Ng B., Burt M. Isolated single lung perfusion with doxorubicin is effective in eradicating soft tissue sarcoma lung metastases in a rat model. J Thorac Cardiovasc Surg. 1994 Jan;107(1):50–54. [PubMed] [Google Scholar]
  42. de Wilt J. H., Manusama E. R., van Tiel S. T., van Ijken M. G., ten Hagen T. L., Eggermont A. M. Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats. Br J Cancer. 1999 Apr;80(1-2):161–166. doi: 10.1038/sj.bjc.6690335. [DOI] [PMC free article] [PubMed] [Google Scholar]