Abstract
Background: Chemotherapy resistance is probably multifactorial; hence, we assessed the feasibility of adding to carboplatin 6 concurrent resistance modulators in 53 patients with resistant cancers.
Methods: Pentoxifylline and dipyridamole were added to carboplatin 400 mg/m2 in cohort 1, and metronidazole was also given in cohort 2. Mannitol and saline were administered in each cohort with the theoretical objective of improving carboplatin delivery to tumors by reducing blood viscosity. Because of excessive toxicity in cohort 2, cohort 3 received the same modulators as in cohort 2 but with a reduced dose of carboplatin (200 mg/m2). Subsequent patients had the following drugs added to those in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5), ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 modulators along with carboplatin 300 mg/m2.
Results: Thrombocytopenia was excessive in early cohorts with a carboplatin dose of 400 mg/m2, but was minimal at lower doses. Other toxicity was generally tolerable and reversible, particularly at carboplatin doses ≤ 300 mg/m2, although gastrointestinal and neurological toxicity tended to worsen as additional modulators were added. No major responses (but 4 minor responses) were seen in this patient population with heavily pretreated or primarily resistant cancers.
Conclusions: Acceptable doses for phase II studies are carboplatin 300 mg/m2, 20% mannitol 250 ml plus normal saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/m2/day p.o. from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m2 p.o. q6h × 6 days starting 24 hr before carboplatin, metronidazole (750 mg/m2 p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m2 suppository p.r. 12 hr and immediately before, and 6 and 24 hr after carboplatin; and 500 mg/m2 i.v. right after carboplatin), novobiocin 600 mg/m2 p.o. q12h × 6 days starting 24 hr before carboplatin, and tamoxifen 100 mg/m2/day plus ketoconazole 700 mg/m2/day × 3 days starting the day before carboplatin, with oral dexamethasone and ondansetron as antimetics.
Similar content being viewed by others
References
Zijlstra JG, de Vries EGE, Mulder NH: Multifactorial drug resistance in adriamycin-resistant human small-cell lung carcinoma cell line. Can Res 47:1780–1784, 1987
Volm M, Kastel M, Mattern J, Effert T: Expression of resistance factors (p-glycoprotein, glutathione S-transferase-pi, and topoisomerase II) and their inter-relationship to proto-oncogene products in renal cell carcinomas. Cancer 71:3981–3987, 1993
Raaphorst GP, Yang DP, Grewaal D, Stewart D, Goel R, Ng CE: Analysis of mechanisms of cisplatin resistance in three pairs of human tumour cell lines expressing normal and resistant responses to cisplatin. Oncol Rep 2:1037–1043, 1995
de Graeff A, Slebos RJ, Rodenhuis S: Resistance to cisplatin and analogues: mechanisms and potential clinical implications. Cancer Chemother Pharmacol 22:325–332, 1988
van der Zee AG, Hollema HH, de Bruijn HW, Willemse PH, Boonstra H, Mulder NH, Aalders JG, de Vries EG: Cell biological markers of drug resistance in ovarian carcinoma. Gynecol Oncol 58:165–178, 1995
Hamaguchi K, Godwin AK, Yakushiji M, O'Dwyer PJ, Ozols RF, Hamilton TC: Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines. Cancer Res 53:5225–5232, 1993
Clement JJ, Johnson RK: Evaluation of radiosensitizers in combination with chemotherapeutic agents in solid tumors. Int J Rad Oncol Biol Phys 8:631–634, 1982
Roizin-Towle L, Hall EJ, Piro JP: Oxygen dependence for chemosensitization by misonidazole. Br J Cancer 54:919–924, 1986
Murray D, Meyn RE: Effect of misonidazole pretreatment on nitrogen mustard-induced DNA cross-linking in mouse tissues in vivo. Br J Cancer 50:801–808, 1984
Taylor YC, Sawyer JM, Hsu B, Brown JM: Mechanisms of melphalan crosslink enhancement by misonidazole pretreatment. Int J Radiat Oncol Biol Phys 10:1603–1607, 1984
Mahood JS, Wilson RL: Cytotoxicity of metronidazole (Flagyl) and misonidazole (Ro-07-0582): Enhancement by lactate. Br J Cancer 43:350–354, 1981
Stewart DJ, Evans WK: Non-chemotherapeutic agents potentiate chemotherapy efficacy. Can Treat Rev 16:1–40, 1989
Lai S-L, Hwang J, Perng R-P, Whang-Peng J: Modulation of cisplatin resistance in acquired-resistant non-small cell lung cancer cells. Oncol Res 7:31–38, 1995
Efferth T, Fabry U, Glatte P, Osieka R: Expression of apoptosis-related oncoproteins and modulation of apoptosis by caffeine in human leukemic cells. J Cancer Res Clin Oncol 121:648–656, 1995
Aviado DM, Dettelback HR: Pharmacology of pentoxifylline a hemorheologic agent for the treatment of intermittent claudication. Angiology 35:407–417, 1984
Jekunen A, Vick J, Sanga R, Chan TCK, Howell SB: Synergism between dipyridamole and cisplatin in human ovarian cancer cells in vitro. Cancer Res 52:3566–3571, 1992
Ali-Osman F, Berger MS, Rajagopal S, Spence A, Livingston RB: Topoisomerase II inhibition and altered kinetics of nitrosourea and cisplatin-induced DNA interstand cross-links and cytotoxicity in human glioblastoma cells. Cancer Res 53:5663–5668, 1993
Rappa G, Lorico A, Sartorelli AC: Induction of the differentiation of WEHI-3B D+ monomyelocytic leukemia cells by inhibitors of topoisomerase II. Cancer Res 50:6723–6730, 1990
Ayesh S, Shao YM, Stein WD: Co-operative, competitive and non-competitive interactions between modulators of P-glycoprotein. Biochim Biophys Acta 1316:8–18, 1996
Rowlands MG, Budworth J, Jarman M, Hardcastle IR, McCague R, Gescher A: Comparison between inhibition of protein kinase C and antagonism of calmodulin by tamoxifen analogues. Biochem Pharmacol 50:723–726, 1995
McClay EF, Albright KD, Jones JA, Christen RD, Howell SB: Tamoxifen modulation of cisplatin cytotoxicity in human malignancies. Int J Cancer 55:1018–1022, 1993
Sharp SY, Mistry P, Valenti MR, Bryant AP, Kelland LR: Selective potentiation of platinum drug cytotoxicity in cisplatin-sensitive and-resistant human ovarian carcinoma cell lines by amphotericin B. Cancer Chemother Pharmacol 35:137–143, 1994
Siegsmund MJ, Cardarelli C, Aksentijevich I, Sugimoto Y, Pastan I, Gottesman MM: Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells. J Urology 151:485–491, 1994
Robert J: Proposals for concomitant use of several modulators of multidrug resistance in clinics. Anticancer Res 14:2371–2374, 1994
Kim JH, Chung JB, Park IS, Kim BS, Yoo NC, Choi JH, Roh JK, Kim HS, Kwon OH, Lee KS et al.: Combined use of tamoxifen, cyclosporin A, and verapamil for modulating resistance in human hepatocellular carcinoma cell lines. Yonsei Med J 34:35–44, 1993
Lyubimov E, Lan L-B, Pashinsky I, Ayesh S, Stein WD: Saturation reversal of the multidrug pump using many reversers in low-dose combinations. Anti-Cancer Drugs 6:727–735, 1995
Lehnert M, Dalton WS, Roe D, Emerson S, Salmon SE: Synergistic inhibition by verapamil and quinine of P-glycoprotein-mediated multidrug resistance in a human myeloma cell line model. Blood 77:348–354, 1991
Ishida Y, Shimada Y, Shimoyama M: Synergistic effect of cyclosporin A and verapamil on overcoming vincristine resistance of multidrug-resistant cultured human leukemia cells. Jap J Cancer Res 81:834–841, 1990
Hu XF, Martin TJ, Bell DR, de Luise M, Zalcbert JR: Combined use of cyclosporin A and verapamil in modulating multidrug resistance in human leukemia cell lines. Cancer Res 50:2953–2957, 1990
Osann K, Sweet P, Slater LM: Synergistic interaction of cyclosporin A and verapamil on vincristine and daunorubicin resistance in multidrug-resistant human leukemia cells in vitro. Cancer Chemother Pharmacol 30:152–154, 1992
Ross DD, Wooten PJ, Tong Y, Cornblatt B, Levy C, Sridhara R, Lee EJ, Schiffer CA: Synergistic reversal of multidrug-resistance phenotype in acute myeloid leukemia cells in cyclosporin A and cremophor EL. Blood 83:1337–1347, 1994
Brooks SE, Korbut TT, Dupuis NP, Holden SA, Teicher BA: Cytotoxicity of antitumor platinum complexes with L-buthionine-(R,S)-sulfoximine and/or etanidazole in human carcinoma cell lines sensitive and resistant to cisplatin. Cancer Chemother Pharmacol 36:431–438, 1995
Stewart DJ, Goel R, Cripps MC, Yau J, Huan S, Tomiak E, Davies RA, Dulude H, Gallant G: Concurrent use of multiple chemotherapy resistance modulators with etoposide in patients with resistant malignancies. Internat J Oncol 11:709–716, 1997
Stewart DJ, Cripps MC, Goel R et al.: Pilot study of multiple chemotherapy resistance modulators plus epirubicin in the treatment of resistant malignancies. Cancer Chemother Pharmacol, in press
Stewart DJ, Dahrouge S, Agboola O, Girard A: Cranial radiation and concomitant cisplatin and mitomycin-C plus resistance modulators for malignant gliomass. J Neuro-Oncol 32:161–168, 1997
Reed E: Platinum analogs. In: De Vita VT Jr, Hellman S, Rosenberg SA (eds) Cancer: Principles and Practice of Oncology, 4th edition. JB Lippincott Co, Philadelphia, 1993, pp 390–400
McEvoy GK (ed): Novobiocin sodium. In: American Hospital Formulary Service (AHFS) Drug Information 89. American Society of Hospital Pharmacists, Bethesda, MD, 1989, pp 325–326
Gillis MC (ed): Compendium of Pharmaceuticals and Specialties, 31st edition. Canadian Pharmaceutical Association, Ottawa, ON, 1996
Burke AM, Quest DO, Chien S, Cerri C: The effects of mannitol of blood viscosity. J Neurosurg 55:550–553, 1981
Jafar JJ, Johns LM, Mullan SF: The effect of mannitol on cerebral blood flow. J Neurosurg 64:754–759, 1986
Jain RK: Determinants of tumor blood flow: a review. Cancer Res 48:2641–2658, 1988
Bergan T: Antibacterial activity and pharmacokinetics of nitromidazoles. A review. Scand J Infect Dis (Suppl) 46:64–71, 1985
Lau AH, Lam NP, Piscitelli SC, Wilkes L, Danziger LH: Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives. Clin Pharmacokin 23:328–364, 1992
Coyle P, Philcox JC, Rofe AM: Corticosterone enhances the zinc and interleukin-6-mediated induction of metallothionein in cultured rat hepatocytes. J Nutrition 123:1464–1470, 1993
Lybak S, Wennerberg J, Kjellen E, Pero RW: Dose schedule evaluation of metoclopramide as a potentiator of cisplatin and carboplatin treatments of xenografted squamous cell carcinomas of the head and neck. Anti-Cancer Drugs 2:375–382, 1991
Israel R, O'Mara V, Austin B, Bellucci A, Meyer BR: Metoclopramide decreases renal plasma flow. Clin Pharm Therapeut 39:261–264, 1986
Stewart DJ, Dulberg C, Mikhael NZ, Redmond MD, Montpetit VAJ, Goel R: Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods. Cancer Chemother Pharmacol 40:293–308, 1997
Stewart DJ, Dulberg C, Molepo JM, Mikhael NZ, Montpetit VAJ, Redmond MD, Goel R: Factors affecting human autopsy kidney cortex and kidney medulla platinum concentrations after cisplatin. Cancer Chemother Pharmacol 34:14–22, 1994
Lee FYF, Workman P: Altered pharmacokinetics in the mechanism of chemosensitization: Effects of nitroimidazoles and other chemical modifiers on the pharmacokinetics, antitumor activity and acute toxicity of selected nitrogen mustards. Cancer Chemother Pharmacol 17:30–37, 1986
van Warmerdam LJ, Rodenhuis S, ten Bokkel Huinink WW, Maes RA, Beijnen JH: Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin. Cancer Chemother Pharmacol 37:266–270, 1996
Beksac M, Akan H, Koc H, Ilhan O, Erturk S, Guneyli A, Ikizunal Y, Sardas OS: P-glycoprotein expression in refractory hematological neoplasms and circumvention of resistance with verapamil or cyclosporin A containing protocols. Med Oncol & Tumor Pharmacother 9:101–105, 1992
List AF, Spier C, Greer J, Wolff S, Hutter J, Dorr R, Salmon S, Futscher B, Baier M, Dalton W: Phase I/II trial of cyclosporin as a chemotherapy-resistant modifier in acute leukemia. J Clin Oncol 11:1652–1660, 1993
Sotomatsu M, Yugami S-I, Shitara T, Kuroume T: Dipyridamole enhancement of drug sensitivity in acute lymphoblastic leukemia cells. Am J Hematol 43:251–255, 1993
Sonnoveld P, Durie BGM, Lokhorst HM, Marie J-P, Solbu G, Sociu S, Zittoun R, Lowenberg B, Nooter K: Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Lancet 340:255–259, 1992
Chan HSL, Koren G, Thorner PS, Verjee Z, Haddad G, Giesbrecht E, Greenberg ML, Ling V, Gallie BL: Reversal of multidrug resistance (MDR) in retinoblastoma (RB) by cyclosporin A (CsA). Proc Am Soc Clin Oncol 11:375, 1992
Stiff P, Bayer R, Sosman J, Peace D, Rad N, Kinch L: High dose chemotherapy with marrow rescue and cyclosporin A: a combined modality approach to overcome drug resistance in solid tumors. Proc Am Soc Clin Oncol 12:132, 1993
Manetta A, Boyle J, Berman M, DiSaia PJ, Lentz S, Liao SY, Mutch D, Slater L: Cyclosporin enhancement of cisplatin chemotherapy in patients with refractory gynecologic cancer. Cancer 73:196–199, 1994
Baradakji Z, Jolivet J, Langelier Y, Besner JG, Ayoub J: 5-fluorouracil-metronidazole combination therapy in metastatic colorectal cancer. Cancer Chemother Pharmacol 18:140–144, 1986
Dalley D, Brigham B: Phase I/II study of oral etoposide and modulation of drug resistance with ketoconazole (KCZ) in small-cell lung cancer (SCLC). Fourth International Congress on Anti-Cancer Chemotherapy, p 85, Paris 1993
Verweij J, Herweijer H, Oosterom R, van der Burg MEL, Planting ASTh, Seynaeve C, Stoter G, Nooter K: A phase I study of epidoxorubicin in colorectal cancer and the use of cyclosporin-A in an attempt to reverse multidrug resistance. Br J Cancer 64:361–364, 1991
Manzano RG, Alonso G, Foncillas JG, Brugarolas A: Cyclosporin A (CsA) plus doxorubicin (dox) containing chemotherapy in adult anthracycline resistant solid tumors (ARST): a phase I clinical study. Proc Am Soc Clin Oncol 12:A385, 1993
Wilson JKV, Fischer PH, Tutsch K, Remick SG, Grem JL, Bruggink L, Alberti D, Simon K, Trump DL: Dipyridamole modulates methotrexate cytotoxicity: Results of a clinical trial based upon inhibition of nucleoside salvage. Proc Am Soc Clin Oncol 6:36, 1987
Higano C, Livingstone R: Methotrexate (MTX) and oral dipyridamole (DP) in the treatment of refractory solid tumors: A phase I-II study. Proc Am Soc Clin Oncol 6:23, 1987
Murphy BR, Rynard SM, Pennington KL, Grosh W, Loehrer PJ: A phase II trial of vinblastine plus dipyridamole in advanced renal cell carcinoma. Am J Clin Oncol (CCT) 17(1):10–13, 1994
Panella T, Strozyk W, Fine R: Phase I study of alpha-interferon 2b (IFN) with hydroxyurea (HU), tamoxifen (TAM), and streptozotocin (STZ) as combined modulators of drug resistance with BCNU. Proc Am Soc Clin Oncol 14:A402, 1995
Raschko J, Doroshow JH, Ahn C, Carroll M, Akman S, Coluzzi P, Hamasaki V, Leong L, Margolin K, Morgan R: Phase I study of multidrug resistance reversal: Biochemical modulation of etoposide (VP16) and carboplatin (CBDCA) with dipyridamole (DP), prochlorperazine (Comp), and cyclosporin A (CSA). Proc Am Soc Clin Oncol 13:A444, 1994
Wishart GC, Harnett A, Kerr DH, Paul J, Machem MA, Soukop M, Leonard RCF, Kaye SB: A randomised placebo controlled trial of quinidine as a resistance modulators in patients with advanced breast cancer treated with epirubicin. Proc Am Soc Clin Oncol 12:A33, 1993
Stewart DJ, Molepo M, Green RM, Montpetit VAJ, Hugenholtz H, Lamothe A, Mikhael NZ, Redmond MD, Goel R: Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin. Br J Cancer 71:598–604, 1995
Assem M, Bonvalot S, Beltramo JL, Garrido C, Dimanche-Boitrel MT, Genne P, Rebibou JM, Caillot D, Chauffert B: Deleterious effect of serum proteins on the amphotericin B-induced potentiation of cisplatin in human colon cancer cells. Br J Cancer 70:631–635, 1994
Stewart DJ, Raaphorst P, Yau J, Beaubien AR: Active vs. passive resistance, dose-response relationships, high dose chemotherapy, and resistance modulation: a hypothesis. Invest New Drugs 14:115–130, 1996
Stewart DJ, Futter N, Irvine A, Danjoux C, Moors D: Mitomycin-C and metronidazole in the treatment of advanced renal cell carcinoma. Am J Clin Oncol 10:520–522, 1987
Stewart DJ, Maroun JA, Lefebvre B, Heringer R, Crook AF: Mitomycin-C plus metronidazole in advanced carcinoma of the breast. Breast Cancer Res Treat 5:189–194, 1985
Stewart DJ, Maroun JA, Young V, Crook AF, Hopkins HS, Yan RC, Richart MT, Hugenholtz H, Belanger R, Heringer R, Lefebvre B, Laframboise G: Feasibility study of combining metronidazole with chemotherapy. J Clin Oncol 1:17–23, 1983
Stewart DJ, Benoit B, Richard MT, Hugenholtz H, Dennery J, Russell N, Peterson E, Grahovac Z, Belanger G, Maroun JA, Young V: Treatment of malignant gliomas in adults with BCNU plus metronidazole. J Neuro-oncol 2:53–58, 1984
Stewart DJ, Cripps MC, Lamothe A, Laframboise G, Odell P, Gerin-Lajoie J: Doxorubicin plus metronidazole in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck. Am J Clin Oncol 16:113–116, 1993
Stewart DJ, Evans WK, Logan D: Addition of pentoxifylline plus nifedipine to chemotherapy in patients with cisplatin-resistant cancers of the lung and other sites. Am J Clin Oncol 17:313–316, 1994
Goel R, Stewart DJ: Phase I study of alternating cycles of high dose combination chemotherapy with different mechanisms of action to overcome drug resistance. Proc Am Soc Clin Oncol 15:1575, 1996
Stewart DJ, Goel R, Gertler S, Huan S, Yau J, Tomiak E, Cripps C, Prosser A, Soltys K: Multiple chemotherapy drugs with differing mechanisms of action to overcome passive resistance. Proc Am Soc Clin Oncol 15:405, 1996
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stewart, D.J., Goel, R., Cripps, M.C. et al. Multiple resistance modulators combined with carboplatin for resistant malignancies: A pilot study. Invest New Drugs 15, 267–277 (1997). https://doi.org/10.1023/A:1005993705237
Issue Date:
DOI: https://doi.org/10.1023/A:1005993705237