Relationship between expression of topoisomerase II isoforms and chemosensitivity in choroidal melanoma.
Choroidal melanoma has a high mortality rate and responds poorly to existing chemotherapy, but unexpected ex vivo sensitivity of a subset of these tumours to topoisomerase II inhibitors has been noted. Since chemoresistance may be mediated by the molecular phenotype of tumours, immunohistochemistry has been used to study the expression of both isoforms of topoisomerase II (alpha and beta) in 29 choroidal melanomas for which chemosensitivity assay data for doxorubicin or mitoxantrone are also available. Of these, eight tumours were topoisomerase II beta-positive and 11 were topoisomerase II alpha-positive. Recent studies showing genetic abnormality (often monosomy of chromosome 3) in choroidal melanoma suggest that loss of immunostaining could be due to genomic loss rather than down-regulation of topoisomerase II beta in these tumours. There was no convincing excess of anthracycline resistance in the topoisomerase II beta-negative group. Addition of topoisomerase II alpha, MDR1 (11/17 positive), LRP (16/28 positive), and MRP (5/29 positive) data in multivariate analysis did not reliably predict sensitivity or resistance. Vincristine chemosensitivity showed no relation to MDR1, LRP or MRP in 18 tumours tested. While it is possible that some tumours which do express topoisomerase II beta may respond to anthracyclines, the molecular basis of resistance or sensitivity to anthracyclines or vincristine in uveal melanoma is complex and remains incompletely understood.
Satherley
K
K
Department of Pathology, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK.
de Souza
L
L
Neale
M H
MH
Alexander
R A
RA
Myatt
N
N
Foss
A J
AJ
Hungerford
J L
JL
Hickson
I D
ID
Cree
I A
IA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D002830:Choroid Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology*; D008875:Middle Aged; D008942:Mitoxantrone / Q000494:pharmacology / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000378:metabolism*; D011237:Predictive Value of Tests; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; D009363:Neoplasm Proteins; D014750:Vincristine; D004317:Doxorubicin; D008942:Mitoxantrone; D004264:DNA Topoisomerases, Type I