Abstract
We have studied the therapeutic efficacy of131I-labelled monoclonal antibody 123C3 in human small-cell lung carcinoma xenografts established from the NCI-H69 cell line in nude mice. Several radiation does were administered intraperitoneally and different treatment schedules were tested. The maximal tolerated dose, 2×500 μCi, resulted in complete remission of tumours smaller than 200 mm3 and long-lasting remission (more than 135 days) of the larger tumours. In control experiments, treatment with unlabelled monoclonal antibody 123C3 did not affect the tumour growth rate, while the effect of radiolabelled non-relevant, isotype-matched, monoclonal antibody M6/1 was minor and transient. Regrowth of the tumours occurred in all cases and could not be attributed to loss of neural cell adhesion molecule (NCAM) expression. Tumour recurrence is probably caused by insufficient radiation dosage. Radiation-induced toxicity was monitored by assessment of weight and bone marrow examination. Weight loss was observed in all treatment groups, but the mice regained their initial weight within 14 days, except for the group receiving the highest radiation dose (3×600 μCi). In this group all mice died as a result of radiotoxicity. Of the mice injected with 600 μCi radiolabelled control antibody, 50% died within 2 weeks after administration. Apparently the higher uptake of the radiolabelled monoclonal antibody in the tumour reduced systemic radiation toxicity.
Key words: NCAM, Monoclonal antibodies, Radioimmunotherapy
References
- 1.Ihde DC. Staging evaluation and prognostic factors in small-cell lung cancer. In: Aisner J, editor. Lung cancer. New York: Churchill Livingstone; 1985. p. 241. [Google Scholar]
- 2.Malaise EP, Fertil B, Deschavanne PJ, Chavandra N, Brock WA. Initial slope of radiation survival curves is characteristic of the origin of primary and established cultures of human tumor cells and fibroblasts. Radiat Res. 1987;111:319. [PubMed] [Google Scholar]
- 3.Carney DN, Mitchell JB, Kinsella TJ. In vitro radiation and chemotherapy sensitivity of established cell lines of human small cell lung cancer and its large cell morphological variants. Cancer Res. 1983;43:2806. [PubMed] [Google Scholar]
- 4.Wessels BW, Vesella RL, Palme DF, Berkopec JM, Smith GK, Bradley EW. Radiobiological comparison of external beam irradiation and radioimmunotherapy in renal cell carcinoma xenografts. Int J Radiat Oncol Biol Phys. 1989;50:1257. doi: 10.1016/0360-3016(89)90534-8. [DOI] [PubMed] [Google Scholar]
- 5.Duschesne GM, Peacock JH, Steel GG. The acute in vitro and in vivo radiosensitivity of human lung tumour lines. Radiother Oncol. 1986;7:353. doi: 10.1016/s0167-8140(86)80066-4. [DOI] [PubMed] [Google Scholar]
- 6.Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, Crawford SM, Burgess JM, Petry NA, Butchko GM, Glenn SD, Wahl RL. Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N. Engl J Med. 1993;329:459. doi: 10.1056/NEJM199308123290703. [DOI] [PubMed] [Google Scholar]
- 7.Goldenberg DM, Horowitz JA, Sharkey RM, Hall TC, Murthy S, Goldenberg H, Lee RE, Stein R, Siegel JA, Izon DO, Burger K, Swayne LC, Belisle E, Hansen HJ, Pinsky CM. Targeting, dosimetry and radioimmunotherapy of B-cell lymphomas with iodine-131-labelled LL2 monoclonal antibody. J Clin Oncol. 1991;9:548. doi: 10.1200/JCO.1991.9.4.548. [DOI] [PubMed] [Google Scholar]
- 8.Lashford L, Jones D, Pritchard J, Gordon I, Breatnach F, Kemshead JT. Therapeutic application of radiolabelled monocloncal antibody UJ13A in children with disseminated neuroblastoma. NCI Monogr. 1987;3:53. [PubMed] [Google Scholar]
- 9.Meredith RF, Johnson TK, Plott G, Macey DJ, Vessella RL, Wilson LA, Breitz HB, Williams LE. Dosimetry of solid tumors. Med Phys. 1993;20:583. doi: 10.1118/1.597053. [DOI] [PubMed] [Google Scholar]
- 10.Meredith RF, Khazaeli MB, Liu T, Plott G, Wheeler RH, Russell C, Colcher D, Schlom J, Shochat D, LoBuglio AF. Dose fractionation of radiolabelled antibodies in patients with metastatic colon cancer. J Nucl Med. 1992;33:1648. [PubMed] [Google Scholar]
- 11.Beverley PCL, Souhami RL, Bobrow L. Results of the central data analysis. Lung Cancer. 1988;4:15. [PMC free article] [PubMed] [Google Scholar]
- 12.Moolenaar CEC, Muller EJ, Schol DJ, Figdor CG, Bock E, Bitter-Suermann D, Michalides RJAM. Expression of neural cell adhesion molecule related sialoglycoprotein in small cell lung cancer and neuroblastoma cell lines H69 and CHP-212. Cancer Res. 1990;50:1102. [PubMed] [Google Scholar]
- 13.Reference deleted
- 14.Schol DJ, Mooi WJ, van der Gugten AA, Wagenaar SjSc, Hilgers J. Monoclonal antibody 123C3, identifying small-cell carcinoma phenotype in lung tumors, recognizes mainly, but not exclusively, endocrine and neuron-supporting normal tissues. Int J Cancer. 1988;43(Suppl 2):34. doi: 10.1002/ijc.2910410711. [DOI] [PubMed] [Google Scholar]
- 15.Lindmo T, Bovan E, Cuttita F, Fedorko J, Bunn PA., Jr Determination of immunoreactive fraction of radiolabelled monoclonal antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Methods. 1984;72:77. doi: 10.1016/0022-1759(84)90435-6. [DOI] [PubMed] [Google Scholar]
- 16.Hunter WM, Greenwood FC. Preparation of iodine-131-labelled growth hormone of high specific radioactivity. Nature. 1962;194:495. doi: 10.1038/194495a0. [DOI] [PubMed] [Google Scholar]
- 17.The TH, Feltkamp TEW. Conjugation of fluorescein isothiocyanate to antibodies. Immunology. 1970;18:865. [PMC free article] [PubMed] [Google Scholar]
- 18.Gazdar AF, Carney DN, Russel EK, Sims HL, Baylin SB, Bunn PA, Guccion JG, Minna JD. Establishment of continuous, clonable cultures of small-cell carcinoma of the lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res. 1980;40:3502. [PubMed] [Google Scholar]
- 19.Badger CC, Krohn KA, Peterson AV, Shulman H, Bernstein ID. Experimental radiotherapy of murine lymphoma with131I-labelled anti-Thy1.1 monoclonal antibody. Cancer Res. 1985;45:1536. [PubMed] [Google Scholar]
- 20.Dillman LT. Radionuclide decay schemes and nuclear parameters for use in radiation-dose estimation. MIRD pamphlet 4. New York: The Society of Nuclear Medicine; 1969. [PubMed] [Google Scholar]
- 21.Molthoff CFM, Pinedo HM, Schlüper HMM, Boven E. Influence of dose and schedule of the therapeutic efficacy of131I-labelled monoclonal antibody 139H2 in a human ovarian cancer xenograft model. Int J Cancer. 1992;50:474. doi: 10.1002/ijc.2910500324. [DOI] [PubMed] [Google Scholar]
- 22.Beaumier PL, Venkatesan P, Vanderhyden JL, Burgua WD, Kunz LL, Fritzberg AR, Abrams PG, Morgan AC., Jr 186Re radioimmunotherapy of small cell lung carcinoma xenografts in nude mice. Cancer Res. 1991;51:676. [PubMed] [Google Scholar]
- 23.Hosono M, Endo K, Hosono MN, Kobayashi H, Shirato M, Sakahara H, Ueda R, Konishi J. Treatment of small-cell lung cancer xenografts with iodine-131-anti-neural cell adhesion molecule monoclonal antibody and evaluation of absorbed dose in tissue. J Nucl Med. 1984;35:296. [PubMed] [Google Scholar]
- 24.Wheldon TE, O'Donoghue JA, Barrett A, Michalowski AS. The curability of tumours of differing size by targeted radiotherapy using131I or90Y. Radiat Oncol. 1991;21:91. doi: 10.1016/0167-8140(91)90080-z. [DOI] [PubMed] [Google Scholar]
- 25.Ihde DC, Bilek FS, Cohen MH, Bunn PA, Eddy J, Minna JD. Response to thoracic radiotherapy in patients with small cell carcinoma of the lung after failure of combination chemotherapy. Radiology. 1979;132:443. doi: 10.1148/132.2.443. [DOI] [PubMed] [Google Scholar]
- 26.Husmann M, Pietsch T, Fleischer B, Weisgerber C, Bitter-Suermann D. Embryonal neural cell adhesion molecules on human natural killer cells. Eur J Immunol. 1989;19:1761. doi: 10.1002/eji.1830190935. [DOI] [PubMed] [Google Scholar]