A molecular cytogenetic approach to studying platinum resistance.
The technique of comparative genomic hybridisation (CGH) has until recently been used to screen for common genomic abnormalities in fresh tumour material; it has identified previously unrecognised regions of amplification associated with poor prognosis subtypes of breast cancer and lymphoma. Our group has applied this technique to resistant cell lines and their sensitive counterparts in order to define chromosomal abnormalities associated with acquired drug resistance. We have demonstrated the applicability of this technique to the study of drug resistance using cell lines with known mechanisms of resistance. The ability to detect novel genomic alterations in cell lines with novel mechanisms of resistance was also demonstrated. We subsequently examined the CGH profiles of seven different cell lines made resistant to three platinum analogues and showed the most consistent abnormalities to involve over-representation of regions 4q and 6q. More recently, we have applied the CGH technique to a series of testicular germ cell tumours (TGCTs) collected as formalin-fixed paraffin-embedded biopsy specimens from patients, both pre- and post-therapy using a platinum-based regimen (POMB/ACE). Previous reports have shown over-representation of X, 7q, 8q and 12p and loss of 13q to occur in 25% of primary TGCTs. Over-representation of 12p was confirmed in the majority of these biopsy samples; deletion of 13q was noted in the initial biopsies of several patients. We also demonstrated alterations of 4p, 4q, 5q and 6q in this series of patients. Newly acquired deletions of 2q and 18q and amplifications of 8q were frequently observed in post-chemotherapy samples from resistant tumours. The CGH studies on these patients with TGCT will not only enable us to correlate our observations on clinical material with those from long-term cell lines, but should also identify sites of key genes involved in clinical platinum resistance.
Hiorns
L R
LR
Department of Experimental Haematology, St. Bartholomew's and Royal London School of Medicine, UK.
Seckl
M J
MJ
Paradinas
F
F
Sharp
S Y
SY
Skelton
L A
LA
Brunstrom
G
G
Newlands
E S
ES
Kelland
L R
LR
Leyland-Jones
B
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002869:Chromosome Aberrations; D002877:Chromosomes, Human; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods*; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology; D017671:Platinum Compounds / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C403613:CB 30865; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D011799:Quinazolines; C110525:amminedichloro(2-methylpyridine)platinum(II); D004317:Doxorubicin; C081294:satraplatin; D002945:Cisplatin