Abstract
Combinations of chemotherapy and interleukin-2 (IL-2) aimed at improving therapeutic efficacy in cancer patients have generally proved disappointing. Although chemotherapy blocks tumor growth and sometimes boosts immune functions, most drugs are immunosuppressive, at least transiently. Therefore, it is reasonable to assume that maximal exploitation of the immunostimulatory and antitumor activity of both modalities requires careful coordination of chemotherapy and IL-2 timing. We analyzed the temporal effect of 5-fluorouracil (5-FU, 100–120 mg/kg), cyclophosphamide (CY, 100 mg/kg), Adriamycin (8 mg/kg) and dacarbazine (100 mg/kg) on the activation of natural killer/lymphokine-activated killer (NK/LAK) cells by IL-2 in several strains of euthymic mice and in athymic nude mice. Following in vivo or in vitro exposure to IL-2 1–15 days after chemotherapy, the total lytic activity of the spleen and the number of LAK precursors (LAK-p) were measured. In euthymic mice injected with IL-2 (5×104 Cetus units twice daily for 4–5 days), 5-FU augmented (up to 37-fold, days 1–9) and CY reduced (up to day 6) LAK activity, as compared with that in the IL-2 control. In bulk cultures containing IL-2 (1000 CU/ml, 3–4 days), both 5-FU and CY reduced LAK activity of euthymic mice splenocytes for up to 6 days after chemotherapy, which was followed on day 9 by full recovery. In splenocytes of nude mice, 5-FU increased and CY diminished LAK activation in bulk cultures, starting 3 days after chemotherapy. In athymic mice, 5-FU markedly augmented the total number of LAK-p/spleen (up to 30-fold, days 3–9), as determined by limiting-dilution cultures with IL-2 (for 7–8 days). In euthymic mice, in contrast, LAK-p levels decreased for up to 6–9 days after treatment with 5-FU, Adriamycin or dacarbazine, later recovering to pretreatment levels, whereas CY markedly increased LAK-p (up to 15-fold) when administered 6–12 days before limiting-dilution culture initiation. The effect of chemotherapy on LAK and NK activity was essentially similar. In other experiments, a subset of asialoGM1-LAK-p was found in the spleens of 5-FU-treated mice, but not in untreated mice. Our results suggest that the immunomodulatory effect of chemotherapy on NK/LAK activity in mice is variable and largely depends on the drug itself, the interval between chemotherapy and IL-2 administration, the strain of mice and the assay used.
Similar content being viewed by others
References
Arinaga S, Akiyoshi T, Tsuji H (1986) Augmentation of the generation of cell-mediated cytotoxicity after a single dose of Adriamycin in cancer patients. Cancer Res 46: 4213–4216
Atkins M, Demchak P, Mier J, Robert N, Sznol M (1990) Phase II study of alternating interleukin-2 (IL-2) and cisplatin (CDDP) with WR-2721 (WR) in metastatic melanoma (abstract). Proc Am Soc Clin Oncol 9: 186
Ballas ZK (1986) Lymphokine-activated killer (LAK) cells. I. Differential recovery of LAK, natural killer cells, and cytotoxic T lymphocytes after a sublethal dose of cyclophosphamide. J Immunol 137: 2380–2384
Berd D, Mastrangelo MJ (1988) Effect of low dose cyclophosphamide on the immune system of cancer patients: depletion of CD4+, 2H4+ suppressor-induced T-cells. Cancer Res 48: 1671–1675
Blair S, Flaherty LE, Valdivieso M, Redman B (1991) Comparison of high dose interleukin-2 (HD IL-2) with combined chemotherapy/low dose IL-2 (chemo/IL-2) in metastatic malignant melanoma (MMM) (abstract). Proc Am Soc Clin Oncol 10: 294
Bubenik J, Simova J, Bubenikova D (1992) Interleukin 2 and cancer. Folia Biol (Praha) 38: 155–169
Bukowski RM, Sergi JS, Budd GT, Murthy S, Tubbs R, Gibson V, Bauer L, Stanley J, Gautam S, Finke J (1991) Phase I trial of continous infusion interleukin-2 and doxorubicin in patients with retractory malignancies. J Immunother 10: 432–439
Cramer DV, Harnaha JB, Herberman RB (1989) The use of 5-fluorouracil to enhance natural killer activity in rat bone marrow. Transplant Proc 21: 3275–3276
Dillman RO, Oldham RK, Barth NM, Birch R, Arnold J, West WH (1990) Recombinant interleukin-2 and adoptive immunotherapy alternated with dacarbazine therapy in melanoma: a National Biotherapy Study Group trial. J Natl Cancer Inst 82: 1345–1349
Eggermont AMM, Sugarbaker PH (1988) Efficacy of chemoimmunotherapy with cyclophosphamide, interleukin-2 and lymphokine activated killer cells in an intraperitoneal murine tumour model. Br J Cancer 58: 410–414
Fiedler W, Jasmin C, De Mulder PH, Pyrhonen S, Palmer PA, Franks CR, Oskam R, Hossfeld DK (1992) A phase II study of sequential recombinant interleukin-2 followed by dacarbazine in metastatic melanoma. Eur J Cancer 28: 443–446
Flaherty LE, Liu PY, Fletcher WS, Goodwin JW, Balcerzak SP, Daniels D, Stephens RL, Sondak VK (1992) Dacarbazine and outpatient interleukin-2 in treatment of metastatic malignant melanoma: phase II Southwest Oncology Group trial. J Natl Cancer Inst 84: 893–894
Gazit Z, Weiss DW, Shouval D, Yechezkeli M, Schirrmacher V, Notter M, Walter J, Kedar E (1992) Chemo-adoptive immunotherapy of nude mice implanted with human colorectal carcinoma and melanoma cell lines. Cancer Immunol Immunother 35: 135–144
Giordano M, Palermo MS, Isturiz MA (1985) Enhancement of phagocytosis by different anti-neoplastic drugs. Int J Immunopharmacol 7: 19–23
Herberman RB (1987) Lymphokine-activated killer cell activity. Immunol Today 8: 178–181
Hosokawa M, Sawamura Y, Morikage T, Okada F, Xu ZY, Morikawa K, Itoh K, Kobayashi H (1988) Improved therapeutic effects of interleukin 2 after the accumulation of lymphokine-activated killer cells in tumor tissue of mice previously treated with cyclophosphamide. Cancer Immunol Immunother 26: 250–256
Isacson R, Kedar E, Barak V, Gazit Z, Yurim O, Kalichman I, Ben-Bassat H, Biran S, Schlesinger M, Franks CR, Roest GJ, Palmer PA, Shiloni E (1992) Chemoimmunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response. Immunol Lett 33: 127–134
Katsanis E, Bausero MA, Ochoa AC, Loeffler CM, Blazar BR, Leonard AS, Anderson PM (1991) Importance in timing of cyclophosphamide on the enhancement of interleukin-2-induced cytolysis. Cancer Immunol Immunother 34: 74–78
Kedar E, Klein E (1992) Cancer immunotherapy: are the results discouraging? Can they be improved? Adv Immunol 59: 245–322
Kedar E, Ben-Aziz R, Shiloni E (1988) Therapy of advanced solid tumors in mice using chemotherapy in combination with interleukin-2 with or without lymphokine-activated killer cells. Isr J Med Sci 24: 494–504
Kedar E, Ben-Aziz R, Epstein E, Leshem B (1989) Chemo-immunotherapy of murine tumors using interleukin-2 (IL-2) and cyclophosphamide. IL-2 can facilitate or inhibit tumor growth depending on the sequence of treatment and the tumor type. Cancer Immunol Immunother 29: 74–78
Kedar E, Rutkowski Y, Leshem B (1992) Chemo-immunotherapy of murine solid tumors: enhanced therapeutic effects by interleukin-2 combined with interferon and the role of specific T cells. Cancer Immunol Immunother 35: 63–68
Kim R, Lafreniere R, Borkenhagen K, Bryant LD (1989) Induction of cytotoxicity from fresh splenocytes after in vivo administration of cyclophosphamide. Importance of long-term culture with high-dose recombinant interleukin-2. Cancer Immunol Immunother 30: 283–288
Kiyohara T, Taniguchi K, Kubota S, Koga S, Sakuragi T, Saitoh Y (1988) Induction of lymphokine-activated killet-like cells by cancer chemotherapy. J Exp Med 168: 2355–2360
Lindemann A, Hoeffken K, Schmidt RE, Diehl V, Kloke O, Gamm H, Hayungs J, Oster W, Boehm M, Franks CR (1989) A multicenter trial of interleukin-2 and low-dose cyclophosphamide in highly chemotherapy-resistant malignancies. Cancer Treat Rev 16 [Suppl A]: 53–57
LoRusso PM, Aukerman SL, Polin L, Redman BG, Valdivieso M, Biernat L, Corbett TH (1990) Antitumor efficacy of interleukin-2 alone and in combination with Adriamycin and dacarbazine in murine solid tumor systems. Cancer Res 50: 5876–5882
Lotze MT, Rosenberg SA (1991) Interleukin-2: clinical applications. In: DeVita VT, Hellman S, Rosenberg SA (eds) Biologic therapy of cancer. Lippincott, Philadelphia, pp 159–177
Maccubbin DL, Cohen SA, Ehrke MJ (1990) Indomethacin modulation of Adriamycin-induced effects on multiple cytolytic effector functions. Cancer Immunol Immunother 31: 373–380
Maccubbin DL, Wing KR, Mace KF, Ho RLX, Ehrke MJ, Mihich E (1992) Adriamycin-induced modulation of host defenses in tumor-bearing mice. Cancer Res 52: 3572–3576
MacDonald HR, Cerottini JC, Ryser JE, Maryanski JL, Taswell C, Widmer MB, Brunner KT (1980) Quantitation and cloning of cytolytic T lymphocytes and their precursors. Immunol Rev 51: 93–123
Mace K, Mayhew E, Mihich E, Ehrke MJ (1988) Alterations in murine host defense functions by Adriamycin or liposomeencapsulated Adriamycin. Cancer Res 48: 130–136
Mantovani A, Luini W, Peri G, Vecchi A, Spreafico F (1978) Effect of chemotherapeutic agents on natural cell-mediated cytotoxicity in mice. J Natl Cancer Inst 61: 1255–1261
Migliorati G, Cannarile L, Herberman RB, Bartocci A, Stanley ER, Riccardi C (1987) Role of interleukin 2 (IL-2) and hemopoietin-1 (H-1) in the generation of mouse natural killer (NK) cells from primitive bone marrow precursors. J Immunol 138: 3618–3625
Mihich E, Ehrke MJ (1991) Immunomodulation by anticancer drugs. In: DeVita VT, Hellman S, Rosenberg SA (eds) Biologic therapy of cancer. Lippincott, Philadelphia, pp 776–786
Mitchell MS (1988) Combining chemotherapy with biological response modifiers in treatment of cancer. J Natl Cancer Inst 80: 1445–1450
Mitchell MS (1992) Chemotherapy in combination with biomodulation: a 5-year experience with cyclophosphamide and interleukin-2. Semin Oncol 19: 80–87
Mokyr MB, Dray S (1987) Interplay between the toxic effects of anticancer drugs and host antitumor immunity in cancer therapy. Cancer Invest 5: 31–38
Mule JJ, Rosenberg SA (1991) Interleukin-2: pre-clinical trials. In: DeVita VT, Hellman S, Rosenberg SA (eds) Biologic therapy of cancer. Lippincott, Philadelphia, pp 142–158
Nanbara S, Arinaga S, Akiyoshi T (1989) Augmentation of the generation of lymphokine-activated killer cells after a single dose of mitomycin C in cancer patients. Cancer Immunol Immunother 29: 237–241
North RJ (1984) The murine antitumor immune response and its therapeutic manipulation. Adv Immunol 35: 89–155
Oldham RK, Stark J, Barth NM, Hoogstraten B, Brown CH, O'Connor T, Dupere S, Birch R (1991) Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group trial. Mol Biother 3: 74–78
Onodera H, Somers SS, Guillou PJ (1990) Paradoxical effects of 5-FU/folinic acid on lymphokine-activated killer (LAK) cell induction in patients with colorectal cancer. Br J Cancer 62: 1042–1046
Paciucci PA, Ryder JS, Holland JF (1990) Correlation between clinical activity of IL-2 and antitumor effects in vitro during the first week of therapy (abstract). Proc Am Soc Clin Oncol 9: 201
Paciucci PA, Bekesi JG, Ryder JS, Odchimar R, Chahinian PA, Holland JF (1991) Immunotherapy with IL2 by constant infusion and weekly doxorubicin. Am J Clin Oncol 14: 341–348
Papa MZ, Yang JC, Vetto JT, Shiloni E, Eisenthal A, Rosenberg SA (1988) Combined effects of chemotherapy and interleukin-2 in the therapy of mice with advanced pulmonary tumors. Cancer Res 48: 122–129
Papadopoulus NEJ, Howard JG, Murray JL, Cunningham J, Plager C, Legha S, Reuben J, Gutterman JU, Benjamin RS (1990) Phase II DTIC and interleukin-2 (IL-2) trial for metastatic malignant melanoma (abstract). Proc. ASCO 9: 277
Reid I, Sharpe I, Maxwell W, McDevitt J, Franks CR, Tanner WA, Monson JR (1992) A phase 2 trial of recombinant interleukin-2 and 5-fluorouracil in patients with metastatic colorectal carcinoma. Eur J Surg Oncol 18: 591–598
Rinchart JJ, Triozzi PL, Lee MH, Aldrich W (1990) The effect of intensive chemotherapy and recombinant human IL-2 (rhIL-2) in a murine tumor model (abstract). Proc Am Assoc Cancer Res 31: 277
Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233: 1318–1321
Santoni A, Riccardi C, Sorci V, Herberman RB (1980) Effects of Adriamycin on the activity of mouse natural killer cells. J Immunol 124: 2329–2335
Sarneva M, Vujanovic NL, Van Den Brink MRM, Herberman RB, Hiserodt JC (1989) Lymphokine-activated killer cells in rats: generation of natural killer cells and lymphokine-activated killer cells from bone marrow progenitor cells. Cell Immunol 118: 448–457
Shiloni E, Pouillart P, Janssens J, Splinter T, Di Peri T, Symann M, Roest GJ, Palmer PA, Franks CR (1989) Sequential dacarbazine chemotherapy followed by recombinant interleukin-2 in metastatic melanoma. A pilot multicenter phase I–II study. Eur J Cancer Clin Oncol 25 [Suppl 3]: S45-S49
Silagi S, Schaefer AE (1986) Successful immunotherapy of mouse melanoma and sarcoma with recombinant interleukin-2 and cyclophosphamide. J Biol Response Mod 5: 411–422
Spicer DV, Kelley A, Herman R, Dean G, Stevenson L, Mitchell MS (1992) Low-dose recombinant interleukin-2 and low-dose cyclophosphamide in metastatic breast cancer. Cancer Immunol Immunother 34: 424–426
Stoter G, Aamdal S, Rodenhuis S, Cleton FJ, Iacobelli S, Franks CR, Oskam R, Shiloni E (1991) Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study. J Clin Oncol 9: 1687–1691
Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47: 187–376
Tsuchiya Y, Matsutani M, Inoue M, Sato S, Asano T, Yajima M (1991) Effect of a glucan, sizofiran, on natural-killer activity of 5-fluorouracil-treated murine bone marrow cells. Cancer Immunol Immunother 34: 17–23
Verdi CJ, Taylor CW, Croghan MK, Dalke P, Meyskens FL, Hersh EM (1992) Phase I study of low-dose cyclophosphamide and recombinant interleukin-2 for the treatment of advanced cancer. J Immunother 11: 286–291
Wolmark N, Sicker D, Yee L, Hiserodt JC, Salup RR (1990) Successful chemoimmunotherapy of murine mammary adenocarcinoma using human recombinant interleukin 2 and doxorubicin hydrochloride (abstract). Proc Am Assoc Cancer Res 31: 268
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gazit, Z., Kedar, E. Chemotherapy-induced modulation of natural killer and lymphokine-activated killer cell activity in euthymic and athymic mice. Cancer Immunol Immunother 38, 243–252 (1994). https://doi.org/10.1007/BF01533515
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01533515