Abstract
The human tumor cloning assay (HTCA) has been available for preclinical and clinical applications for the last 11 years. This article examines the usefulness of that assay both in the practice of clinical oncology and in the development of new antineoplastic agents. In the area of prediction of response of an individual patient's tumor to a particular antineoplastic agent, in a total of 2274 correlations in a variety of clinical trials, the assay has shown a remarkably good ability to predict whether a patient's tumor would respond to a particular agent (percent true positives 69%; percent true negatives 91%). However, despite this ability to predict these responses, the assay has not yet been accepted for general clinical use, because there have not been rigorous trials to prove the assay will improve patient survival. These rigorous clinical trials are now underway. In the area of drug development, the HTCA has been used to screen for new antineoplastic agents as well as to pinpoint tumor types against which the new agent will be active in phase II clinical trials. As will be seen in this review, the HTCA has been most successful in this area.
Similar content being viewed by others
References
Von Hoff DD, Weisenthal I: In vitro methods to predict for patient response to chemotherapy. In: Garattini S, Goldin A, Hawking F, et al. (eds) Advanced Pharmacology Chemotherapy. Academic Press, New York, 1980, pp 133–156
Park CH, Bergsagel DE, McCulloch EA: Mouse myeloma tumor stem cells: a primary cell culture assay. JNCI 46: 411–422, 1971
Ogawa M, Bergsagel DE, McCulloch EA: Chemotherapy of mouse myeloma: quantitative cell culture predictive of response in vivo. Blood 41: 7–15, 1973
Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells. Science 197: 461–463, 1977
Hamburger AW, Salmon SE: Primary bioassay of human myeloma stem cells. J Clin Invest 60: 846–854, 1977
Salmon SE, Hamburger AW, Soehnlen B, Durie BG, Alberts, Moon TE: Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs. N Engl J Med 298: 1321–1327, 1978
Courtenay VD, Mills J: An in vitro colony assay for human tumours grown in immune-suppressed mice and treated in vivo with cytotoxic agents. Br J Cancer 37: 261–268, 1978
Von Hoff DD, Swenerton KD, Hetaner L, Gafney E, Rivkin S, Schuchart S, ColtmanJr CA: Long distance transportation of specimens for human tumor cloning. Stem Cells 2: 122–128, 1982
Von Hoff DD, Casper J, Bradley E, Trent JM, Hodach A, Reichert C, Makuch R, Altman A: Direct cloning of human neuroblastoma cells in soft agar culture. Cancer Res 40: 3591–3597, 1980
Hamburger AW, Salmon Se, Kim MB, Trent JM, Soehnlen BJ, Alberts DS, Schmidt HJ: Direct cloning of human ovarian carcinoma cells in agar. Cancer Res 38: 3438–3444, 1978
Slocum HK, Pavelic ZP, Rustum YM, Creaven PJ, Karakousis C, Takita H, Greco WR: Characterization of cells obtained by mechanical and enzymatic means from human melanoma, sarcoma, and lung tumors. Cancer Res 41: 1428–1434, 1981
Shoemaker RH, Wolpert-DeFilippes MK, Kern DH, Lieber MM, Makuch RW, Melnick NR, Miller WT, Salmon SE, Simon RM, Venditti JM, Von Hoff DD: Application of a human tumor colony-forming assay to new drug screening. Cancer Res 45: 2145–2153, 1985
Hanauske U, Hanauske A-R, Marshall MH, Muggia VA, Von Hoff DD: Biphasic effect of vanadium salts on in vitro tumor colony growth. Int J Cell Cloning 5: 170–178, 1987
Selby P, Buick RN, Tannock I: A critical appraisal of the ‘Human Tumor Stem-Cell Assay’. N Engl J Med 308: 129–134, 1983
Sondak VK, Bertelsen CA, Tanigawa N, Hildebrand-Zanki SU, Morton DL, Korn EL, Kern DV: Clinical correlations with chemosensitivities measured in a rapid Thymidine Incorporation Assay. Cancer Res 44: 1725–1728, 1984
Baker FL, Spitzer G, Ajani JA, Brock WA, Lakeman J, Pathak S, Tomasovic B, Thielvoldt D, Williams M, Vines C, Tofilon P: Drug and radiation sensitivity measurements of successful primary monolayer culturing of human tumor cells using cell adhesive matrix and supplemented medium. Cancer Res 46: 1263–1274, 1986
Ajani JA, Baker FL, Spitzer G, Kelly A, Brock W, Tomasovic B, Singletary SF, McMurtrey M, Plager C: Comparison between clinical response and in vitro drug sensitivity of primary human tumors in the adhesive tumor cell culture system. J Clin Oncol 5: 1912–1921, 1987
Von Hoff D: Plating efficiencies of human tumors in capillaries versus petri dishes. In: Salmon SE, Trent JM (eds) Human Tumor Cloning. Grune and Stratton, Orlando, 1984, pp 153–161
Von Hoff DD, Forseth BJ, Huong M, Buchok JB, Lathan B: Improved plating efficiencies for human tumors cloned in capillary tubes versus petri dishes. Cancer Res 46: 4012–4017, 1986
Park CH, Savin MA, Hoogstraten B, Amare M, Hathaway P: Improved growth of in vitro colonies in human acute leukemia with feeding culture method. Cancer Res 37: 4595–4601, 1977
Von Hoff DD: In vitro predictive testing: The Sulfonamide era. Int J Cell Cloning 5: 179–190, 1987
Alberts DS, Chen HSG, Soehnlen B, Salmon SE, Surwitt EA, Young L, Moon TE: In vitro clonogenic assay for predicting response of ovarian cancer to chemotherapy. Lancet 2: 340–342, 1980
Rosenblum ML, Dougherty DV, Wilson CB: Human brain tumor cell sensitivity testing—preliminary correlation with patient treatment. Proc Am Assoc Cancer Res and Am Soc Clin Oncol 21: 254, 1980
Natale R, Yagoda A, Molander D: In vitro and in vivo sensitivity of human bladder carcinoma: Correlation with phase II tumors of AMSA, PALA, and methotrexate. Proc Am Assoc Cancer Res and Am Soc Clin Oncol 21: 297, 1980
Possinger K, Hartenstein R, Ehrhart H: In vitro resistance of tumors to cytostatics. Onkologie 3: 297–300, 1980
Von Hoff DD, Casper J, Bradley E, Sandbach J, Jones D, Makuch R: Association between human tumor colony forming assay results and response of an individual patient's tumor to chemotherapy. Am J Med 70: 1027–1032, 1981
Plasse T, Shapiro M, Ohnuma T, Friedman N, Competiello L, Ambinder EP, Holland JF: In vitro culture of enzymatically disaggregated tumors as semisolid agar. Proc Am Assoc Cancer Res 22: 392, 1981
Meyskens FLJr, Moon TE, Dana B, Gilmartin E, Cosey WJ, Chen HSG, Franks DH, Young L, Salmon SE: Quantitation of drug sensitivity by human metastatic melanoma colony-forming units. Br J Cancer 44: 787–797, 1981
Epstein LB, Marcus SG: Review of experience with interferon and drug sensitivity testing of ovarian carcinoma in semisolid agar culture. Cancer Chemother Pharmacol 6: 273–277, 1981
Tisman G, Wu STG: The clinical and laboratory evaluation of a modified tumor stem cell assay for the in vitro determination of human tumor cell drug sensitivity. Proc Am Assoc Cancer Res and Am Soc Clin Oncol 22: 364, 1981
Ballet F, Petit J, Poupon R, Darnis F: Soft agar clonogenic assay for predicting chemosensitivity of human tumor cells from malignant effusions. Biomedicine 35: 177–178, 1981
Tihon C, Curry ME, Issell BF, Anderson PN, Speer JF: A method for improved sample utilization and availability for human tumor cloning assay. Proc Am Assoc Cancer Res 22: 226, 1981
Carney DN, Gazdur AF, Minna JD: In vitro chemosensitivity of clinical specimens and established cell lines of smallcell lung cancer. Stem Cells 1: 296, 1981
Ludwig H, Fritze H: Individual chemotherapy in multiple myeloma by cytostatic drug sensitivity testing of colony-forming cells. Anticancer Res 1: 329–334, 1981
Natale RB, Kushner B: Use of the human tumor cloning assay (HTCA) to assess chemotherapy sensitivity of transitional cell carcinoma (TCC) of the bladder. Proc Am Assoc Cancer Res and Am Soc Clin Oncol 22: 464, 1981
Natale RB, Kushner B: Applications of the human tumor cloning assay (HTCA) to ovarian cancer (OC). Proc Am Assoc Cancer Res and Am Soc Clin Oncol 22: 156, 1981
Rupniak TH, Marks P, Watkins S, et al.: Studies on the drug sensitivities of human tumour cells obtained directly from biopsy material. Twelfth International Congress of Chemotherapy, July 19–24, 1984, Florence, Italy. The International Society of Chemotherapy 301, 1981
Kaiser LR, Kern DH, Campbell MA, Mann DD, Holmes EC: In vitro assessment of antineoplastic therapy. J Thorac Cardiovasc Surg 82: 538–541, 1981
Ahmann FR, Meyskens FL, Moon TE, Durie BMG, Salmon SE: In vitro chemosensitivities of human tumor stem cells to the phase II drug 4′-(9-Acridinylamino) methone sulfon-m-aniside and prospective in vivo correlations. Cancer Res 42: 4495–4498, 1982
Alberts DS, Mackel C, Pocelinko R, Salmon SE: Phase I clinical investigation of 9,10-Anthracenedicarboxaldehyde Bis [(4,5-dihydro-1 H-imidazol-2-yl)hydrazone] Dihydrochloride with correlative in vitro human tumor clonogenic assay. Cancer Res 42: 1170–1175, 1982
Mann BD, Kern DH, Giuliano AE, Burk MW, Campbell MA, Kaiser L, Morton DL: Clinical cologenic assay. Arch Surg 117: 33–36, 1982
Tveit KM, Fodstad O, Lotsberg J, Vaage S, Pihl A: Colony growth and chemosensitivity in vitro of human melanoma biopsies. Relationship to clinical parameters. Int J Cancer 29: 533–538, 1982
Banerjee TK, Marx JJ, Spencer SK, Tiffany E: Human tumor stem cell clonogenic assay sensitivity in malignant tumors and clinical correlation. Wisc Med J 81: 19–22, 1982
Naaktgeboren N, Theunissen J, Sips H, Roobol C, Bernheim JL: In vitro assessment of the therapeutic value of antineoplastic agents. Acta Clinica Belgica 37: 271–280, 1982
Welander CE, Homesley HD, Jobson VW: In vitro chemotherapy testing of gynecologic tumors: basis for planning therapy? Am J Obstet Gynecol 147: 188–195, 1983
Rey A, Cupissol D, Favier F, Rucheton M, Serrou B: Prognostic evaluation of human tumor cell in vitro cloning assay. Biomed 36: 42–45, 1982
Carney DH, Broder L, Edelstern M, Gazdar AF, Hansen M, Havemann K, Matthews MJ, Sorenson G, Videlov L: Experimental studies of the biology of human small cell lung cancer. Cancer Treat Rep 67: 27–35, 1983
Gau TC, Natale RB, Ensminger W, Gyves J, Niederhuber J: A prospective double blind test of the capacity of the human tumor cloning assay to predict the in vivo sensitivity of hepatic tumors treated with single agents administered by continuous arterial infusion with a totally implantable pump. Proc Am Soc Clin Oncol 2: 123, 1983
Kern DH, Bertelsen CA, Mann BD, Campbell MA, Morton DL, Cochran AJ: Clinical application of the clonogenic assay. Ann Clin Lab Sci 13: 10–15, 1983
Von Hoff DD, Clark GM, Stogdill BJ, Sarosdy MF, O'Brien MT, Casper JT, Mattox DE, Page DP, Cruz AB, Sandbach JF: Prospective clinical trial of a human tumor cloning system. Cancer Res 43: 1926–1931, 1983
Mann HD, Storm FK, Morton DL, Bertelson CA, Korn FL, Kaiser LR, Kern DH: Predictability of response to clinical thermo chemotherapy by the clonogenic assay. Cancer 52: 1389–1394, 1983
Durie BGM, Young L, Salmon SE: Human myeloma stem cell culture: interrelationship between drug sensitivity, cell kinetics and patients survival duration. Blood 61: 929–934, 1983
Foster BJ, Jayadpour N, Ozols RF: Potential therapeutic and diagnostic applications of the growth of testicular cancer in soft agar. Int J Cell Cloning 1: 2–14, 1983
MacKie RM, Gaukroger JM, Wilson L, Gold J: Experience with the colony-forming (stem cell) assay of in vitro chemosensitivity in the management of patients with advanced malignant melanoma. Cancer Treat Res 68: 1185–1188, 1984
Greenberg BR, Salmon SE: Human tumor clonogenic assay in patients with unknown primary carcinoma. J Clin Oncol 2: 46–50, 1984
Shimizu E, Saijo N, Kanzawa F, Hoshi A, Eguchi K, Shinkas T, Tominaga K, Sasaki Y, Fujita J, Nomori H, Futami H, Miyazawa N: Correlation between drug sensitivity determined by clonogenic cell assay and clinical effect of chemotherapy in patients with primary lung cancer. Gann 75: 1030–1035, 1984
Sondak VK, Bertelson CA, Tanigawa N, Hildebrand-Zanki SU, Morton DL, Korn EL, Kern DH: Clinical correlations with chemosensitivities measured in a rapid thymidine incorporation assay. Cancer Res 44: 1725–1728, 1984
Meyskens FLJr, Loescher L, Moon TE, Tkasugi B, Salmon SE: Relation of in vitro colony survival to clinical response in a prospective trial of single-agent chemotherapy for metastatic melanoma. J Clin Oncol 2: 1223–1228, 1984
Alonso K: Human tumor stem cell assay—a prospective clinical trial. Cancer 54: 2475–2479, 1984
Parker RL, Welander CE, Homesley HD, Jobson VW, Kawamoto EH: Use of the human tumor stem cell assay to study chemotherapy sensitivity in cancer of the cervix. Obst and Gynecol 64: 412–416, 1984
Bertelsen CA, Sondak VK, Mann BD, Korn EL, Kern DH: Chemosensitivity testing of human solid tumors. Cancer 53: 1240–1245, 1984
Strayer DR, Weisband J, Carter WA, Brodsky I: Sensitivity of renal cell carcinoma to leukocyte Interferon in the human tumor clonogenic assay and clinical correlations. In: Salmon SE, Trent JM (eds) Human Tumor Cloning. Grune and Stratton, Orlando, 1984, pp 585–593
Ajani JA, Spitzer G, Baker F, Umbach GE, Tomasovic B, Sahu SK, Hug VM: Human tumor cloning assay with prospective clinical correlations and association between in vitro sensitivity and the number of drugs tested. In: Salmon SE, Trent JM (eds) Human Tumor Cloning. Grune and Stratton, Orlando, 1984, pp 595–605
Jones SE, Dean JC, Young LA, Salmon SE: The human tumor clonogenic assay in human breast cancer. J Clin Oncol 3: 92–97 1985
Dittrich CH, Jakes ZR, Wrba F, Havelec L, Haas O, Spona J, Holzner H, Kolb R, Moser K: The human tumour cloning assay in the management of breast cancer patients. Br J Cancer 52: 197–203, 1985
Ajani J, Baker F, Spitzer G, Brock W, Thielvoldt D, Tomasovic B, McMurtrey M, Plager C: Adhesive tumor cell culture system (ATCCS): preliminary results of clinical correlations. Proc Am Assoc Cancer Res 27: 411, 1986
Link LH, Aigner KR, Kuehn W, Schwemmle K, Kern DH: Prospective correlative chemmosensitivity testing in high-dose intraarterial chemotherapy for liver metastases. Cancer Res 46: 4837–4840, 1986
Hug V, Thames H, Hortobagyi G, Finders M: Chemosensitivities of human clonogenic breast tumor cells. Eur J Cancer Clin Oncol 22: 971–981, 1986
Rozencweig M, Staquet M: Predictive tests for the response to cancer chemotherapy: limitations related to the prediction of rate events. Cancer Treat Rep 68: 611–612, 1984
Selker HP: Clinical prediction rules. N Engl J Med 314: 714–715, 1986
Welander CE, Morgan TM, Homesley HD: Multiple factors predicting responses to combination chemotherapy in patients with ovarian cancer. In: Salmon SE, Trent JM (eds) Human Tumor Cloning. Grune and Stratton, Orlando, 1984, pp 521–534
Von Hoff DD, Turner J, Forseth B, Sandbach J, Piccart M, Muggia F, Clark G: Prospective randomized clinical trial of the capillary cloning system versus a clinicians choice. Proc Am Sci Clin Oncol 4: 30, 1985
Carney DN, Gazdor AF, Minna JD: Positive correlation between histological tumor involvement and generation of tumor cell colonies in agarose specimens taken directly from patients with small-cell carcinoma of the lung. Cancer Res 40: 1820–1823, 1980
Pollard EB, Tio F, Myers JW, Clark G, Coltman CAJr, Von Hoff DD: Utilization of a human tumor cloning system to monitor for marrow involvement with small cell carcinoma of the lung. Cancer Res 41: 1015–1020, 1981
Cheung N-KV, Von Hoff DD, Strandjord SE, Coccia PF: Detection of neuroblastoma cells in bone marrow using GD2 specific monoclonal antibodies. J Clin Oncol 4: 363–369, 1986
Bertancello I, Bradley TR, Campbell JJ: Limitations of the clonal agar assay for assessment of primary human tumour biopsies. Br J Cancer 45: 803–811, 1982
Rey AA, Capissol D, Ursule E: Prognostic value of the human tumor clonogenic assay (HTCA) in patients with ovarian carcinomas. Int J Cell Cloning 1: 289–290, 1983
Sutherland CM, Mather FJ, Carter RD, Cerise EJ, Krementz ET: Breast cancer as analyzed by the human tumor stem cell assay. Surgery 94: 370–375, 1983
Hug V, Rashid R, Blumenschein G, Spitzer G: Clonogenic in vitro growth and histologic grading of primary breast tumors. Int J Cell Cloning 3: 143–148, 1985
Aapro MJ, Eliason JF, Kramer F, Alberts P: Colony formation in vitro as a prognostic indicator for primary breast cancer. J Clin Oncol 5: 890–896, 1987
Mattox DE, Von Hoff DD: In vitro stem cell assay in head and neck squamous cancer. Am J Surg 140: 527–530, 1980
Mattox DE, Von Hoff DD, Clark GM, Aufdenorte TB: Factors that influence the growth of head and neck squamous carcinoma in the soft agar cloning assay. Cancer 53: 1736–1740, 1984
Johns ME, Mills SE: Cloning efficiency—a possible prognostic indicator in squamous cell carcinoma of the head and neck. Cancer 52: 1401–1404, 1983
Miller OL, Grover FL, Trinkle JK, Bennett EV, Clark G, Coltman CAJr, Von Hoff DD: Growth of human tumor colonies in soft agar is a prognostic factor for patients with lung cancer. Surg Forum 34: 435–437, 1983
Lathan B, Von Hoff DD, Elslager E: Use of a human tumor cloning system to evaluate analogs of methotrexate and Mitoxantrone. Cancer Treat Rep 68: 733–738, 1984
Salmon SE, Young L, Soehnlen B, Liu R: Antitumor activity of Esorubicin in human tumor clonogenic assay with comparison to doxorubicin. J Clin Oncol 2: 282–286, 1984
Von Hoff DD, Coltman CAJr, Forseth B: Activity of Mitoxantrone in a human tumor cloning system. Cancer Res 41: 1853–1855, 1981
Von Hoff DD, Coltman CAJr, Forseth B: Activity of 9–10 anthracenedicarboxaldehyde bis ((4,5-dihydro-1H-imidazol-2-yl) hydrazone) dihydrochloride (CL216,942) in a human tumor cloning system: Leads for phase II trials in man. Cancer Chemother Pharmacol 6: 141–144, 1981
Hutton JJ, Von Hoff DD: Cytotoxicity of 2-chlorodeoxyadenosine in a human tumor colony-forming assay. Cancer Drug Delivery 3: 115–122, 1986
Brown T, Flemming T, Macdonald J: A randomized trial of two schedules of trimetrexate (TMTX) versus 5-fluorouracil (5FU) in colorectal carcinoma: A Southwest Oncology Group Study. Proc Am Soc Clin Oncol 7: 109, 1988
Melink TJ, von Hoff DD, Kuhn JG, Hersh MR, Sternson LA, Patton TF, Siegler R, Boldt DH, Clark GM: Phase I evaluation and pharmacokinetics of Tiazofurin (2-β-D-Ribofuranosylthiazole-4-Carboxamide: NSC 286193). Cancer Res 45: 2859–2865, 1985
Scheithauer W, Clark GM, Salmon SE, Dorda W, Shoemaker RH, Von Hoff DD: Model for estimation of clinically achievable plasma concentrations for investigational anticancer drugs in man. Cancer Treat Rep 70: 1379–1382, 1986
Davis LE, Alberts DS, Plezia PM, Roe DJ, Griswold DP: Predictive model for plasma concentration-versus-time profiles of investigational anticancer drugs in patients. JNCI 80: 815–819, 1988
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Von Hoff, D.D. Human tumor cloning assays: Applications in clinical oncology and new antineoplastic agent development. Cancer Metast Rev 7, 357–371 (1988). https://doi.org/10.1007/BF00051376
Issue Date:
DOI: https://doi.org/10.1007/BF00051376