Summary
Apart from clinical trials, mitoxantrone (MX) is rarely used in breast cancer (BC) due to the anticipated anthracycline cross-resistance. We have examined this drug versus doxorubicin (DOX) using data obtained fromin vitro microplate ATP tumor chemosensitivity assays (ATP-TCA) of BC cells which were derived from 55 chemotherapy-naive patients at time of primary surgery. Both drugs were tested at 6 different concentrations ranging from 6.25% to 200% peak plasma concentrationin vivo (PPC). Differences between DOX and MX observed for mean IC50, IC90, and a sensitivity index (SI) were not statistically significant.In vitro response rates were 44% for DOX and 52% for MX. 34 of 52 eligible assays (65%) showed comparable activity of both drugs whereas a lack of cross-resistance was observed in the remaining 18 (35%) tumors as indicated by differences for SI. Cumulative concentration-response plots of tumors respondingin vitro with a ≥ 50 percent or ≥ 90 percent tumor cell inhibition showed a strong dose-dependence for both DOX and MX at concentrations which normally can be achieved within clinical tumors (i.e. 6.25%-50% PPC). At higher concentrations, however, cytotoxicity of DOX and MX could not be improved by furtherin vitro dose escalation. Moreover, a substantial proportion of BC specimens (DOX: 48.1%; MX: 40.4%) did not experience a ≥ 90 tumor cell inhibition at 200% PPC. In conclusion,in vitro results obtained by ATP-TCA indicate that there is no cross-resistance between MX and DOX in a substantial proportion of BC patients. This may be clinically useful and suggests that combinations including MX should be tested in patients clinically resistant to DOX containing regimens. Since both drugs produced sigmoidal concentration-response curves, dose escalation beyond a certain point may not produce increased sensitivity.
References
Fisher B, Carbone P, Economou SG: L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: A report of early findings. N Engl J Med 292: 117–122, 1975
Bonadonna G, Brusamolino E, Valagussa P: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294: 405–410, 1976
Bonadonna G, Valagussa P: The contribution of medicine to the primary treatment of breast cancer. Cancer Res 48: 2314–2324, 1988
Bonadonna G: Evolving concepts in the systemic adjuvant treatment of breast cancer. Cancer Res 52: 2127–2137, 1992
Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. The results of 20 years of follow-up. N Engl J Med 332: 901–906, 1995
Jones RB, Holland JF, Bhardwaj S et al.: A phase I–II study of intensive-dose adriamycin for advanced breast cancer. J Clin Oncol 5: 172–177, 1987
Ahman DL, Schaid D, Bisel HF: The effect on survival of initiating chemotherapy in advanced breast cancer: polychemotherapy versus single drug. J Clin Oncol 5: 1928–1932, 1987
Kardinal CG: Chemotherapy of breast cancer. In: Perry MC (ed.) The Chemotherapy Source Book. Williams & Wilkins, Baltimore, 1992, pp 949–988
Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG, Shibata H, Paterson AHG, Sutherland CM, Robert NJ, Ager PJ, Levy L, Wolter J, Wozniak T, Fisher ER, Deutsch M: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8: 1483–1496, 1990
Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood W, Barcos M, Henderson C: C-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330: 1260–1266, 1994
Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results. JA-MA 273: 542–547, 1995
Dukart G, Iatropoulos MJ, Yacobi A: Comment on mitoxantrone. Drug Intell Clin Pharmacy 19: 216–218, 1985
Henderson IC, Allegra JC, Woodcock T, Wolff S, Bryan S, Cartwright K, Dukart G, Henry D: Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol 7: 560–571, 1989
Heidemann E, Steinke B, Hartlapp J, Schumacher K, Possinger K, Kunz S, Neeser E, von Ingersleben G, Hossfeld D, Caffier H, Souchon R, Waldmann R, Blümner E, Clark J: Prognostic subgroups: The key factor for treatment outcome in metastatic breast cancer. Results of a three-arm randomized multicenter trial comparing doxorubicin, epirubicin and mitoxantrone each in combination with cyclophosphamide. Onkologie 16: 344–353, 1993
Smith IE: Mitoxantrone (novantrone): A review of experimental and early clinical studies. Cancer Treat Rev 10: 103–115, 1983
Neidhart JA, Gochnour D, Roach R, Hoth D, Young D: A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4: 672–677, 1986
Andersson M, Mouridsen HT: Mitoxantrone as single agent chemotherapeutic agent for advanced breast cancer: The phase II trial experience. In: Mouridsen HT, Arlin ZA (eds) The Role of Mitoxantrone in Malignant Diseases. Pharma-Libri Publ, Chicago, 1987, pp 31–47
Ahmann F, Garewal H, Schifman R, Celniker A, Rodney S: Intracellular adenosine triphosphate as a measure of human cell viability and drug modulated growth.In vitro Cell Develop Biol 23: 474–480, 1987
Andreotti PE, Linder D, Hartmann DM, Becker K, Herbst K, Cree IA, Bruckner HW: ATP tumor chemosensitivity assay application for solid tumors and leukemias. In: Szalay A, Kricka LJ, Stanley PE (eds) Chemiluminescence and Bioluminescence. Status Report. John Wiley & Sons: Chichester, 1993, pp 271–275
Hunter EM, Sutherland LA, Cree IA, Dewar JA, Preece PE, Wood RAB, Linder D, Andreotti PE: Heterogeneity of chemosensitivity in human breast carcinoma: Use of an adenosine triphosphate (ATP) chemiluminescence assay. Eur J Surg Oncol 19: 242–249, 1993
Petty RD, Sutherland LA, Hunter EM, Cree IA: Comparison of MTT and ATP-based assays for the measurement of viable cell number. J Biolumin Chemilumin 10: 29–34, 1995
Sevin BU, Peng Z, Perras J, Ganjei P, Penalver G, Averette H: Application of an ATP bioluminescence assay in human tumor chemosensitivity testing. Gynecol Oncol 31: 191–204, 1988
Andreotti PE, Thornwaite JT, Morse IS: ATP tumor chemosensitivity assay. In: Stanley PE, Kricka LJ (eds) Bioluminescence and Chemiluminescence: Current Status. John Wiley & Sons, Chichester, 1991, pp 417–420
Cree IA, Pazzagli M, Mini E, Mazzei T, Hunter EMM, Sutherland LA, Pinzani P, Gerli A, Andreotti PE: Methotrexate chemosensitivity by ATP luminescence in human leukemia cell lines and breast cancer primary cultures: comparison of the TCA-100 assay with a clonogenic assay. Anti-Cancer Drugs 6: 398–404, 1995
Andreotti PE, Linder D, Hartmann DM, Cree IA, Pazzagli M, Bruckner HW: TCA-100 Tumor Chemosensitivity Assay: Differences in sensitivity between cultured tumour cell lines and clinical studies. J Biolumin Chemilumin 9: 373–378, 1994
Kurbacher CM, Bruckner HW, Andreotti PE, Kurbacher JA, Sa G, Krebs D:In vitro activity of titanocenedichloride versus cisplatin in four ovarian carcinoma cell lines evaluated by a microtitre plate ATP bioluminescence assay. Anti-Cancer Drugs 6: 697–704, 1995
Andreotti PE, Cree IA, Kurbacher CM, Hartmann DM, Linder D, Harel G, Gleiberman I, Caruso PA, Ricks SH, Bruckner HW: Sensitivity testing of human tumors using a microplate ATP assay. In: Campbell AK, Kricka LJ, Stanley PE (eds) Bioluminescence and Chemiluminescence. Fundamentals and Applied Aspects. John Wiley & Sons, Chichester, 1994, pp 403–406
Kurbacher CM, Mallmann P, Kurbacher JA, Saß G, Andreotti PE, Rahmun A, Hübner H, Krebs D:In vitro activity of titanocenedichlorideversus cisplatin and doxorubicin in primary and recurrent epithelial ovarian cancer. Anticancer Res 14: 1961–1966, 1994
Koechli OR, Avner BP, Sevin BU, Avner B, Perras JP, Robinson DS, Averette HE: Application of the ATP-Cell Viability Assay in human breast cancer chemosensitivity testing. A report on the first results. J Surg Oncol 54: 119–125, 1993
Cree IA, Sutherland LA, Hunter EMM, Subedi AMC, James EA, Dewar JA, Preece PE, Andreotti PE: Validation of the TCA-100 tumour chemosensitivity assay (Abstract). J Tumor Marker Oncol 9: 42, 1994
Andreotti PE, Cree IA, Kurbacher CM, Hartmann DM, Linder D, Harel G, Gleiberman I, Caruso PA, Ricks SH, Untch M, Sartori C, Bruckner HW: Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma. Cancer Res 55: 5276–5282, 1995
Bosanquet AG: Stability of solutions for antineoplastic agents during preparation and storage forin vitro assays. II. Assay methods, adriamycin and other anti-tumour antibiotics. Cancer Chemother Pharmacol 17: 1–10, 1986
Hunter EM, Sutherland LA, Cree IA, Subedi AM, Hartmann D, Linder D, Andreotti PE: The influence of storage on cytotoxic drug activity in an ATP-based chemosensitivity assay. Anti-Cancer Drugs 5: 171–176, 1994
Alberts DS: Tabular summary of pharmacokinetic parameters relevant toin vitro drug assay. In: Salmon SE (ed.) Cloning of Human Tumor Stem Cells. Alan R Liss Inc, New York, 1980, pp 351–359
Dalton WS, Alberts DS: Pharmacokinetics of mitoxantrone. In: Mouridsen HT, Arlin ZA (eds) The Role of Mitoxantrone in Malignant Diseases. PharmaLibri Publ, Chicago, 1987, pp 5–18
Silverman RA: Calculus with Analytical Geometry. Prentice Hall Inc., New Yersey, 1985, pp 416–418
Von Hoff DD, Clark GM, Weiss GR, Marshall MH, Buckok JB, Knight WA III, LeMaistre CF: Use ofin vitro dose response effects to select antineoplastics for high-dose or regional administration regimens. J Clin Oncol 4: 1827–1834, 1986
Maltere P, Martin M, Piot M, Manoux D, Maillart P, Combe M, Kamioner D, Serin D, Chalmin B, Renaud R, Grapin JP: Neoadjuvant chemotherapy with FNC (fluorouracil, mitoxantrone and cyclophosphamide) in operable locally advanced breast cancer (LABC) allows breast conservation (Abstract). Proc Amer Soc Clin Oncol 14: 92, 1995
Sandbach J, Von Hoff DD, Clark G, Cruz AB, O'Brien M: Direct cloning of human breast cancer in soft agar culture. Cancer 50: 1315–1321, 1982
Jones SE, Dean JC, Young LA, Salmon SE: The human tumor clonogenic assay in breast cancer. J Clin Oncol 3: 92–97, 1985
Koechli OR, Sevin BU, Perras J, Angioli R, Steren A, Rodriguez M, Averette HE: Growth characteristics of non-malignant cells in the ATP-Cell-Viability-Assay. Oncology 51: 35–41, 1994
Riggs CE: Antitumor antibiotics and related compounds. In: Perry MC (ed.) The Chemotherapy Source Book. Williams & Wilkins, Baltimore, 1992, pp 318–358
Fields K, Perkins J, Elfenbein G, Ballester O, Hiemenz J, Goldstein S, Zorsky P, Kronish L: A phase I dose escalation trial of high dose taxol®, novantrone®, and thiotepa (TNT) followed by autologous stem cell rescue (ASCR): Toxicity. (Abstract). Proc Amer Soc Clin Oncol 14: 322, 1995
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kurbacher, C.M., Cree, I.A., Brenne, U. et al. Heterogeneity ofin vitro chemosensitivity in perioperative breast cancer cells to mitoxantroneversus doxorubicin evaluated by a microplate ATP bioluminescence assay. Breast Cancer Res Tr 41, 161–170 (1996). https://doi.org/10.1007/BF01807161
Issue Date:
DOI: https://doi.org/10.1007/BF01807161