Systemic chemotherapy-induced microsatellite instability in the mononuclear cell fraction of women with breast cancer can be reproduced in vitro and abrogated by amifostine.
Microsatellite instability (MSI) induction by alkylating agent-based chemotherapy (ACHT) may underlie both tumor resistance to chemotherapy and secondary leukaemias in cancer patients. We investigated if ACHT could induce MSI in tumor-derived plasma-circulating DNA (pfDNA) and in normal peripheral blood mononuclear (PBMN) cells. We also evaluated if amifostine could interfere with this process in an in-vitro model.



MSI was determined in pfDNA, PBMN cells and urine cell-free DNA (ufDNA) of 33 breast cancer patients before and after ACHT. MCF-7 cells and PBMN from normal donors were exposed in vitro to melphalan, with or without amifostine.



We observed at least one MSI event in PBMN cells, pfDNA or ufDNA of 87, 80 and 80% of patients, respectively. In vitro, melphalan induced MSI in both MCF-7 and normal PBMN cells. In PBMN cells, ACHT-induced MSI occurred together with a significant decrease in the expression of the DNA mismatch repair gene hMSH2. Amifostine decreased hMSH2 expression and also prevented MSI induction only in normal PBMN cells.



ACHT induced MSI in PBMN cells and in tumour-derived pfDNA. Because of its protective effect against ACHT induction of MSI in normal PBMN cells in vitro, amifostine may be a potential agent for preventing secondary leukaemias in patients exposed to ACHT.
Pinto
Jorge L F
JL
ABC Foundations School of Medicine, Santo André, Brazil.
Fonseca
Fernando L A
FL
Marsicano
Sarah R
SR
Delgado
Pamela O
PO
Sant'anna
Aleksandra V L
AV
Coelho
Patrícia G
PG
Maeda
Patríca
P
Del Giglio
Auro
A
D004999:Amifostine / Q000494:pharmacology*; D016587:Antimutagenic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D007938:Leukemia / Q000139:chemically induced / Q000517:prevention & control; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008558:Melphalan / Q000009:adverse effects; D053842:Microsatellite Instability / Q000187:drug effects*; D018895:Microsatellite Repeats / Q000187:drug effects; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D012016:Reference Values
D016587:Antimutagenic Agents; D018906:Antineoplastic Agents, Alkylating; D051718:MutS Homolog 2 Protein; D004999:Amifostine; D008558:Melphalan