TY - JOUR
T1 - The molecular basis of the chemosensitivity of
metastatic cutaneous melanoma to chemotherapy
AU - Parker, Katharine
AU - Glaysher, S.
AU - Polak, M.
AU - Gabriel, F.
AU - Johnson, P.
AU - Knight, L.
AU - Poole, Matthew
AU - Narayanan, A.
AU - Hurren, J.
AU - Cree, I.
N1 - Funders:
Wessex Cancer Trust.
CanTech Ltd.
Applied Biosystems.
Skin Cancer Research Fund.
PY - 2010
Y1 - 2010
N2 - Background. Chemotherapy benefits relatively few
patients with cutaneous melanoma. The assessment of
tumour chemosensitivity by the ATP-based tumour
chemosensitivity assay (ATP-TCA) has shown strong
correlation with outcome in cutaneous melanoma, but
requires fresh tissue and dedicated laboratory facilities.
Aim. To examine whether the results of the ATP-TCA
correlate with the expression of genes known to be
involved in resistance to chemotherapy, based on the
hypothesis that the molecular basis of chemosensitivity
lies within known drug resistance mechanisms.
Method. The chemosensitivity of 47 cutaneous
melanomas was assessed using the ATP-TCA and
correlated with quantitative expression of 93 resistance
genes measured by quantitative reverse transcriptase
PCR (qRT-PCR) in a Taqman Array after extraction of
total RNA from formalin-fixed paraffin-embedded tissue.
Results. Drugs susceptible to particular resistance
mechanisms showed good correlation with genes linked
to these mechanisms using signatures of up to 17 genes.
Comparison of these signatures for DTIC, treosulfan and
cisplatin showed several genes in common. HSP70, at
least one human epidermal growth factor receptor,
genes involved in apoptosis (IAP2, PTEN) and DNA repair
(ERCC1, XPA, XRCC1, XRCC6) were present for these
agents, as well as genes involved in the regulation of
proliferation (Ki67, p21, p27). The combinations tested
included genes represented in the single agent
signatures.
Conclusions. These data suggest that melanoma
chemosensitivity is influenced by known resistance
mechanisms, including susceptibility to apoptosis. Use of
a candidate gene approach may increase understanding
of the mechanisms underlying chemosensitivity to drugs
active against melanoma and provide signatures with
predictive value.
AB - Background. Chemotherapy benefits relatively few
patients with cutaneous melanoma. The assessment of
tumour chemosensitivity by the ATP-based tumour
chemosensitivity assay (ATP-TCA) has shown strong
correlation with outcome in cutaneous melanoma, but
requires fresh tissue and dedicated laboratory facilities.
Aim. To examine whether the results of the ATP-TCA
correlate with the expression of genes known to be
involved in resistance to chemotherapy, based on the
hypothesis that the molecular basis of chemosensitivity
lies within known drug resistance mechanisms.
Method. The chemosensitivity of 47 cutaneous
melanomas was assessed using the ATP-TCA and
correlated with quantitative expression of 93 resistance
genes measured by quantitative reverse transcriptase
PCR (qRT-PCR) in a Taqman Array after extraction of
total RNA from formalin-fixed paraffin-embedded tissue.
Results. Drugs susceptible to particular resistance
mechanisms showed good correlation with genes linked
to these mechanisms using signatures of up to 17 genes.
Comparison of these signatures for DTIC, treosulfan and
cisplatin showed several genes in common. HSP70, at
least one human epidermal growth factor receptor,
genes involved in apoptosis (IAP2, PTEN) and DNA repair
(ERCC1, XPA, XRCC1, XRCC6) were present for these
agents, as well as genes involved in the regulation of
proliferation (Ki67, p21, p27). The combinations tested
included genes represented in the single agent
signatures.
Conclusions. These data suggest that melanoma
chemosensitivity is influenced by known resistance
mechanisms, including susceptibility to apoptosis. Use of
a candidate gene approach may increase understanding
of the mechanisms underlying chemosensitivity to drugs
active against melanoma and provide signatures with
predictive value.
U2 - 10.1136/jcp.2010.080119
DO - 10.1136/jcp.2010.080119
M3 - Article
SN - 0021-9746
VL - 63
SP - 1012
EP - 1020
JO - Journal of Clinical Pathology
JF - Journal of Clinical Pathology
IS - 11
ER -