Abstract
A membrane protein recognized by monoclonal antibody SQM1 was identified in human squamous carcinomas, including those originating in the head and neck (SqCHN), lung and cervix. Cell lines derived from SqCHN of previously untreated patients expressed high amounts of this protein. In contrast, many cell lines established from SqCHN of patients previously treated with chemotherapy and/or radiation showed diminished amounts of this SQM1 protein. The expression of SQM1 antigen was determined in several SgCHN cell lines made resistant by exposure to methotrexate (MTX) in vitro. The parent cell lines all exhibited strong binding to SQM1 antibody. The MTX-resistant sublines showed much lower membrane binding of SQM1. The lowest SQM1 reactivity was found in cell lines with high resistance to MTX and with diminished rate of MTX transport. Some highly MTX-resistant cell lines which had high levels of dihydrofolate reductase, but which retained a high rate of MTX transport, also retained high levels of SQM1 binding. Reduced SQM1 protein was also found in SgCHN cells which developed resistance to the alkylating drug cis-platinum (CDDP) and which showed reduced membrane transport of CDDP. Cell growth kinetics and non-specific antigenic shifts were not responsible for the differences in SQM1 binding between the parent cell lines and their drug-resistant sublines. The finding of a novel protein which is reduced in cells resistant to MTX and CDDP could contribute to our understanding of the basic mechanisms of drug resistance. By detecting SQM1 protein in clinical specimens, it may be possible to monitor the development of drug resistance in tumors.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- SqCHN:
-
Squamous Carcinoma of the Head and Neck
- MTX:
-
Methotrexate
- CDDP:
-
Cis-Platinum
- DHFR:
-
Dihydrofolate Reductase
References
Johns DG, Bertino JR: Folate Antagonists. In: JF Holland and E Frei (eds) Cancer Medicine. Lea and Febiger, PA, 1982,pp.775–790
Kirkwood JM, Canellos GP, Ervin TJ, Pitman SW, Weichselbaum R, Miller D: Increased therapeutic index using moderate dose methotrexate and leucovorin twice weekly vs. weekly high dose methotrexate-leucovorin in patients with advanced squamous carcinoma of the head and neck. Cancer 47: 24–4–2421, 1981
Alt FW, Kellems RE, Schimke RT: Synthesis and degradation of folate reductase in sensitive and methotrexate-resistant lines of S-180 Cells. J Biol Chem 251: 3063–3071, 1976
Rosowsky A, Lazarus H, Yuan GC, Beltz WR, Mangini L, Abelson HT, Modest EJ, Frei E: Effects of methotrexate esters and other lipophilic antifolates on methotrexate-resistant human leukmeic lymphoblasts. Biochem Pharmacol 29:648–652,1980
Frei E, Rosowsky A, Wright JE, Cucchi CA, Lippke JA, Ervin TJ, Jolivet J, Haseltine WA: Development of methotrexate resistance in a human squamous cell carcinoma of the head and neck in culture. Proc Natl Acad Sci USA 81: 2873–2877,1984
Kaufman RJ, Bertino JR, Schimke RT: Quantitation of dihydrofolate reductase in individual parental and methotrexate-resistant murine cells. J Biol Chem 253: 5852–5862, 1978
Rosowsky A, Wright JE, Cucchi CA, Lippke JA, Tantravahi R, Ervin TJ, Frei E: Phenotypic heterogeneity in cultured human head and neck squamous cell carcinoma lines with low-level methotrexate resistance. Cancer Res 45: 6205–6212,1985
Colvin M: Alkylating Drugs. In: B Chabner B (ed), Pharmacologic Principles of Cancer Treatment. Saunders, PA, 1982, pp 276–306
Zwelling LA, Kohn KW: Platinum Complexes. In: B Chabner (ed) Pharmacologic Principles of Cancer Treatment, Saunders, PA, 1982, pp 309–339
Von Hoff DD, Elson D: Cis Platinum. In: AW Prestayko, ST Crooke and SK Carter (eds) Cisplatin: Current Status, Acad Press, New York, 1980, pp 445–458
Teicher BA, Cucchi CA, Lee JB, Flatow JL, Rosowsky A, Frei E: Alkylating Agents: In vitro studies of cross-resistance patterns in human cell lines. Cancer Res. 46: 4379–4383,1986
Boeheim K, Speak JA, Frei E, Bernal SD: SQM1 antibody defines a surface membrane antigen in squamous carcinoma of the head and neck. Int J Cancer 36: 137–142, 1985
Stahel RA, Speak JA and Bernal SD. Murine monoclonal antibody LAM2 defines cell membrane determinant with preferential expression on human lung small-cell carcinoma and squamous-cell carcinomas. Int J Cancer 35: 11–17,1985
Bernal SD, Cualing HM, Stahel RA, Elias A, Mabry M: Immunology of lung cancer. In: PG Abrams and ST Rosen (eds) Immunology of Lung Cancer: Diagnosis and Treatment. Marcel Dekker Inc, New York, 1988, v 37, pp 213–236
Riordan JR, Ling V: Purification of p-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability. J Biol Chem 254:12701–12705,1979
Riordan JR, Ling V: Genetic and biochemical characterization of multi-drug resistance. Pharmac Ther 28: 51–75, 1985
Danks MK, Metzger DW, Ashmun RA, Beck WT: Monoclonal antibodies to glycoproteins of vinca alkaloid-resistant human leukemic cells. Cancer Res 45: 3220–3224, 1985
Bell DR, Gerlach JH, Kartner N, Buick RN, Ling V: Detection of p-glycoprotein in ovarian cancer: A molecular marker associated with multidrug resistance. J Clin One 3: 311–315, 1985
Beidler JL, Peterson RHF: Altered plasma membrane glycoconjugates of Chinese hamster cells with acquired resistance to actinomycin D, daunorubicin, and vincristine. In: AC Sartorelli, JS Lazo and JR Bertino (eds) Molecular Actions and Targets for Cancer Chemotherapeutic Agents, Acad Press, New York, 1981, pp 453–482
Beck WT, Mueller TJ, Tanzer LR: Altered surface membrane glycoproteins in vinca alkaloid resistant human leukemic lymphoblasts, Cancer Res 39: 2070–2076, 1979
Richert N, Akiyama S, Shen DW, Gottesman MM, Pastan I: Multiply drug-resistant human KB carinoma cells have decreased amounts of a 75-kDa glycoprotein. Proc Natl Acad Sci USA 82: 2330–2333, 1985
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bernal, S.D., Speak, J.A., Boeheim, K. et al. Reduced membrane protein associated with resistance of human squamous carcinoma cells to methotrexate and cis-platinum. Mol Cell Biochem 95, 61–70 (1990). https://doi.org/10.1007/BF00219531
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00219531