Platinum agents in the treatment of osteosarcoma: efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines.

2.50
Hdl Handle:
http://hdl.handle.net/10541/80134
Title:
Platinum agents in the treatment of osteosarcoma: efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines.
Authors:
Robson, Helen; Meyer, Stefan; Shalet, Stephen M; Anderson, Elizabeth; Roberts, S; Eden, Tim O B
Abstract:
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 micromol) showed marked variation in cytotoxicity among the three cell lines. EC(50) values for CBDCA in HOS and MG63 cells were approximately two-fold higher than for cDDP and the ratio of AUC(CBDCA) to AUC(cDDP) 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 micromol) 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.
Affiliation:
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. Hgoodman@picr.man.ac.uk
Citation:
Platinum agents in the treatment of osteosarcoma: efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines. 2002, 39 (6):573-80 Med. Pediatr. Oncol.
Journal:
Medical and Pediatric Oncology
Issue Date:
Dec-2002
URI:
http://hdl.handle.net/10541/80134
DOI:
10.1002/mpo.10076
PubMed ID:
12376980
Type:
Article
Language:
en
ISSN:
0098-1532
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorRobson, Helen-
dc.contributor.authorMeyer, Stefan-
dc.contributor.authorShalet, Stephen M-
dc.contributor.authorAnderson, Elizabeth-
dc.contributor.authorRoberts, S-
dc.contributor.authorEden, Tim O B-
dc.date.accessioned2009-09-07T15:04:36Z-
dc.date.available2009-09-07T15:04:36Z-
dc.date.issued2002-12-
dc.identifier.citationPlatinum agents in the treatment of osteosarcoma: efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines. 2002, 39 (6):573-80 Med. Pediatr. Oncol.en
dc.identifier.issn0098-1532-
dc.identifier.pmid12376980-
dc.identifier.doi10.1002/mpo.10076-
dc.identifier.urihttp://hdl.handle.net/10541/80134-
dc.description.abstractBACKGROUND: 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 micromol) showed marked variation in cytotoxicity among the three cell lines. EC(50) values for CBDCA in HOS and MG63 cells were approximately two-fold higher than for cDDP and the ratio of AUC(CBDCA) to AUC(cDDP) 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 micromol) 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.en
dc.language.isoenen
dc.subjectBone Canceren
dc.subjectCultured Tumour Cellsen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshApoptosis-
dc.subject.meshBone Neoplasms-
dc.subject.meshCarboplatin-
dc.subject.meshCell Cycle-
dc.subject.meshCisplatin-
dc.subject.meshDrug Screening Assays, Antitumor-
dc.subject.meshHumans-
dc.subject.meshOsteosarcoma-
dc.subject.meshTumor Cells, Cultured-
dc.titlePlatinum agents in the treatment of osteosarcoma: efficacy of cisplatin vs. carboplatin in human osteosarcoma cell lines.en
dc.typeArticleen
dc.contributor.departmentTumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. Hgoodman@picr.man.ac.uken
dc.identifier.journalMedical and Pediatric Oncologyen

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