Predicting the myelotoxicity of chemotherapy:  the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells.
To assess the value of pretreatment O6-methylguanine-DNA methyltransferase (MGMT) expression in peripheral blood mononuclear cells (PBMCs) in predicting haematological toxicity with O6-alkylating agent chemotherapy, we explored this relationship retrospectively in melanoma patients. Ninety-three patients treated with temozolomide or dacarbazine in four clinical trials were assessed, and a model of the interaction between MGMT expression and haematological toxicity was constructed. Nadir white-cell and platelet counts were related to, and hence could be predicted from, pretreatment MGMT. Leucopenia and thrombocytopenia were more prevalent amongst patients with low pretreatment MGMT, according to the highest grades of toxicity experienced and/or the dose intensity patients could sustain. Addition of interferon to chemotherapy or compression of the temozolomide schedule increased the toxicity. The model also predicts significant myelotoxicity where PBMC MGMT is inactivated, consistent with the experience in the clinic with lomeguatrib and O6-benzylguanine. Determination of MGMT in PBMC can identify patients at greatest risk of toxicity or who are suitable for dose intensification.
Sabharwal
Ami
A
Department of Medical Oncology, University of Oxford, Oxford, UK.
Waters
Rachel
R
Danson
Sarah
S
Clamp
Andrew
A
Lorigan
Paul
P
Thatcher
Nick
N
Margison
Geoffrey P
GP
Middleton
Mark R
MR
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000097:blood* / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012189:Retrospective Studies; D000077204:Temozolomide; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects; D013997:Time Factors
D054316:Biomarkers, Pharmacological; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013792:Thalidomide; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide