Platinum agents in the treatment of osteosarcoma: Efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines
Corresponding Author
H. Robson BSc, PhD
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom.Search for more papers by this authorS. Meyer MD, MRCP
Department of Paediatric Oncology, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorS.M. Shalet MD, FRCP
Department of Endocrinology, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorE. Anderson BSc, PhD
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorS. Roberts
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorO.B. Eden FRCP, FRCPath
Department of Paediatric Oncology, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorCorresponding Author
H. Robson BSc, PhD
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom.Search for more papers by this authorS. Meyer MD, MRCP
Department of Paediatric Oncology, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorS.M. Shalet MD, FRCP
Department of Endocrinology, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorE. Anderson BSc, PhD
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorS. Roberts
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorO.B. Eden FRCP, FRCPath
Department of Paediatric Oncology, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester, United Kingdom
Search for more papers by this authorAbstract
Background
Cisplatin (cDDP), when used either alone or, more often, in combination with other agents, especially adriamycin, achieves a high response rate in osteosarcoma. Its use, however, is limited by severe nephro- and neuro-toxicity. Second generation platinum compounds, most notably carboplatin (CBDCA), have been developed in order to attempt to reduce these dose-limiting toxicities, and thus improve the therapeutic ratio. Studies evaluating the role of combination CT containing CBDCA vs. cDDP have demonstrated differing results depending on the tumor type tested and its role in the treatment of osteosarcoma has yet to be clarified.
Procedure
In this study, we compared the in vitro anti-tumor activity of cDDP and CBDCA in a panel of three human osteosarcoma cell lines (HOS, MG63, and U2OS).
Results
cDDP and CBDCA (0–20 μmol) showed marked variation in cytotoxicity among the three cell lines. EC50 values for CBDCA in HOS and MG63 cells were approximately two-fold higher than for cDDP and the ratio of AUCCBDCA to AUCcDDP varied from 1.8 in the HOS cell line to 2.3 in the MG63 cell line. Exposure of MG63 and HOS cells to either cDDP or CBDCA (1.67 and 13.5 μmol) caused a G2/M cell cycle arrest by 24 hr. Also evident was a sub G1 peak indicative of cell death by apoptosis. U2OS cells were relatively resistant to the cytotoxic effects of both drugs, although a cell cycle arrest in response to DNA damage was observed. This suggests that unlike MG63 and HOS cells, U2OS cells have either a more efficient repair pathway for platinum-induced DNA damage or are able to evade apoptosis. Examination of apoptotic events and cellular recovery demonstrated that both an 8–16-fold higher concentration and longer treatment period for CBDCA compared with cDDP was required to produce equivalent cell death and a loss of the ability of single cell clones to form colonies in both the HOS and MG63, but not the U2OS cell line.
Conclusions
Our findings suggest that CBDCA at a two- to four-fold higher concentration than cDDP has potential therapeutic activity in platinum sensitive osteosarcomas, particularly when cDDP cytotoxicity compromises therapeutic efficacy. Med Pediatr Oncol 2002;39:573–580. © 2002 Wiley-Liss, Inc.
REFERENCES
- 1 Winkler K, Bielack SS, Delling G, et al. Treatment of osteosarcoma: Experience of the Cooperative Osteosarcoma Study Group (COSS). Cancer Treat Res 1993; 62: 269–277.
- 2 Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 1988; 6: 329–337.
- 3 Smith MA, Ungerleider RS, Horowitz ME, et al. Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma [see comments]. J Natl Cancer Inst 1991; 83: 1460–1470.
- 4 Doz F, Pinkerton R. What is the place of carboplatin in paediatric oncology? Eur J Cancer 1994; 30A: 194–201.
- 5 Bajorin DF, Sarosdy MF, Pfister DG, et al. Randomized trial of etoposide and cisplatin vs. etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. J Clin Oncol 1993; 11: 598–606.
- 6 Bokemeyer C, Kohrmann O, Tischler J, et al. A randomized trial of cisplatin, etoposide and bleomycin (PEB) vs. carboplatin, etoposide and bleomycin (CEB) for patients with ‘good-risk’ metastatic non-seminomatous germ cell tumors. Ann Oncol 1996; 7: 1015–1021.
- 7 Horwich A, Sleijfer DT, Fossa SD, et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997; 15: 1844–1852.
- 8 Lokich J, Anderson N. Carboplatin vs. cisplatin in solid tumors: An analysis of the literature [published erratum appears in Ann Oncol 1998 Mar;9(3):341]. Ann Oncol 1998; 9: 13–21.
- 9 Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999; 17: 409–422.
- 10
Ettinger LJ,
Gaynon PS,
Krailo MD, et al.
A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the Children's Cancer Group.
Cancer
1994;
73:
1297–1301.
10.1002/1097-0142(19940215)73:4<1297::AID-CNCR2820730427>3.0.CO;2-# CAS PubMed Web of Science® Google Scholar
- 11
Petrilli AS,
Kechichian R,
Broniscer A, et al.
Activity of intraarterial carboplatin as a single agent in the treatment of newly diagnosed extremity osteosarcoma.
Med Pediatr Oncol
1999;
33:
71–75.
10.1002/(SICI)1096-911X(199908)33:2<71::AID-MPO2>3.0.CO;2-T CAS PubMed Web of Science® Google Scholar
- 12 Ferguson WHM, Link M, Gebhardt M, et al. Carboplatin in the treatment of newly diagnosed metastatic or unresectable osteosarcoma: A Paediatric Oncology Group study (meeting abstract). Proc Am Soc Clin Oncol 1996; 15: A1678.
- 13 Skehan P, Storeng R, Scudiero D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990; 82: 1107–1112.
- 14 Raymond E, Chaney SG, Taamma A, et al. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998; 9: 1053–1071.
- 15 Mimnaugh EG, Yunmbam MK, Li Q, et al. Prevention of cisplatin-DNA adduct repair and potentiation of cisplatin-induced apoptosis in ovarian carcinoma cells by proteasome inhibitors. Biochem Pharmacol 2000; 60: 1343–1354.
- 16 Monks A, Harris ED, Vaigro-Wolff A, et al. UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines. Invest New Drugs 2000; 18: 95–107.
- 17 Lee SI, Brown MK, Eastman A. Comparison of the efficacy of 7-hydroxystaurosporine (UCN-01) and other staurosporine analogs to abrogate cisplatin-induced cell cycle arrest in human breast cancer cell lines. Biochem Pharmacol 1999; 58: 1713–1721.
- 18 Mangioni C, Bolis G, Pecorelli S, et al. Randomized trial in advanced ovarian cancer comparing cisplatin and carboplatin [see comments]. J Natl Cancer Inst 1989; 81: 1464–1471.
- 19 Conte PF, Bruzzone M, Carnino F, et al. Carboplatin, doxorubicin, and cyclophosphamide vs. cisplatin, doxorubicin, and cyclophosphamide: a randomized trial in stage III–IV epithelial ovarian carcinoma. J Clin Oncol 1991; 9: 658–663.
- 20 Taylor AE, Wiltshaw E, Gore ME, et al. Long-term follow-up of the first randomized study of cisplatin vs. carboplatin for advanced epithelial ovarian cancer. J Clin Oncol 1994; 12: 2066–2070.
- 21 Lassen U, Kristjansen PE, Osterlind K, et al. Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up. Ann Oncol 1996; 7: 365–371.
- 22 Muggia FM. Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin. Semin Oncol 1989; 16: 7–13.
- 23 Knox RJ, Friedlos F, Lydall DA, et al. Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res 1986; 46: 1972–1979.
- 24 Takahashi H, Sasaki Y, Saijo N, et al. In vitro colony inhibition of carboplatin against stomach and lung cancer cell lines in comparison with cisplatin. Cancer Chemother Pharmacol 1987; 19: 197–200.
- 25 Los G, Verdegaal E, Noteborn HP, et al. Cellular pharmacokinetics of carboplatin and cisplatin in relation to their cytotoxic action. Biochem Pharmacol 1991; 42: 357–363.
- 26 Ferrari S, Mercuri M, Picci P, et al. Nonmetastatic osteosarcoma of the extremity: Results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic tumor response. Tumori 1999; 85: 458–464.
- 27 Rha SY, Chung HC, Gong SJ, et al. Combined pre-operative chemotherapy with intra-arterial cisplatin and continuous intravenous adriamycin for high grade osteosarcoma. Oncol Rep 1999; 6: 631–637.
- 28 Voute PA, Souhami RL, Nooij M, et al. A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI) [in process citation]. Ann Oncol 1999; 10: 1211–1218.
- 29 Cairo MS, Shen V, Krailo MD, et al. Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report. J Pediatr Hematol Oncol 2001; 23: 30–38.
- 30 Chang AY, Hui L, Asbury R, et al. Ifosfamide, carboplatin and etoposide (ICE) in metastatic and refractory breast. Cancer Chemother Pharmacol 1999; 44 (Suppl): S26–S28.
- 31 Sundquist WI, Lippard SJ, Stollar BD. Monoclonal antibodies to DNA modified with cis- or trans-diamminedichloroplatinum(II). Proc Natl Acad Sci USA 1987; 84: 8225–8229.
- 32 Eastman A. Analysis and quantitation of the DNA damage produced in cells by the cisplatin analog cis-[3H]dichloro-(ethylenediamine)platinum (II). Anal Biochem 1991; 197: 311–315.
- 33 Parker RJ, Eastman A, Bostick-Bruton F, Reed E. Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest 1991; 87: 772–777.
- 34 Ishikawa T, Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem 1993; 268: 20116–20125.
- 35 Evans DL, Tilby M, Dive C. Differential sensitivity to the induction of apoptosis by cisplatin in proliferating and quiescent immature rat thymocytes is independent of the levels of drug accumulation and DNA adduct formation. Cancer Res 1994; 54: 1596–1603.
- 36 Kelland LR. The molecular basis of cisplatin sensitivity/resistance [comment]. Eur J Cancer 1994; 30A: 725–727.
- 37 Timmer-Bosscha H, Mulder NH, de Vries EG. Modulation of cis-diamminedichloroplatinum(II) resistance: a review. Br J Cancer 1992; 66: 227–238.
- 38 Reardon JT, Vaisman A, Chaney SG, et al. Efficient nucleotide excision repair of cisplatin, oxaliplatin, and Bis- aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts. Cancer Res 1999; 59: 3968–3971.
- 39 Miyake H, Hara I, Yamanaka K, et al. Synergistic enhancement of resistance to cisplatin in human bladder cancer cells by overexpression of mutant-type p53 and Bcl-2. J Urol 1999; 162: 2176–2181.
- 40 Piovesan B, Pennell N, Berinstein NL. Human lymphoblastoid cell lines expressing mutant p53 exhibit decreased sensitivity to cisplatin-induced cytotoxicity. Oncogene 1998; 17: 2339–2350.
- 41 Branch P, Masson M, Aquilina G, et al. Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells. Oncogene 2000; 19: 3138–3145.
- 42 Fan S, Smith ML, Rivet DJ, et al. Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res 1995; 55: 1649–1654.
- 43 Tsuchiya H, Mori Y, Ueda Y, et al. Sensitization and caffeine potentiation of cisplatin cytotoxicity resulting from introduction of wild-type p53 gene in human osteosarcoma. Anticancer Res 2000; 20: 235–242.
- 44 Romano JW, Ehrhart JC, Duthu A, et al. Identification and characterization of a p53 gene mutation in a human osteosarcoma cell line. Oncogene 1989; 4: 1483–1488.
- 45 Matsumoto T, Sowa Y, Ohtani-Fujita N, et al. p53-independent induction of Waf1/Cip1 is correlated with osteoblastic differentiation by vitamin D3. Cancer Lett 1998; 129: 61–68.
- 46 Allan LA, Fried M. p53-dependent apoptosis or growth arrest induced by different forms of radiation in U2os cells: p21waf1/Cip1 repression in UV induced apoptosis. Oncogene 1999; 18: 5403–5412.
- 47 Diller L, Kassel J, Nelson CE, et al. p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol 1990; 10: 5772–5781.
- 48
Fajac A,
Da Silva J,
Ahomadegbe JC, et al.
Cisplatin-induced apoptosis and p53 gene status in a cisplatin-resistant human ovarian carcinoma cell line.
Int J Cancer
1996;
68:
67–74.
10.1002/(SICI)1097-0215(19960927)68:1<67::AID-IJC13>3.0.CO;2-3 CAS PubMed Web of Science® Google Scholar
