Detection of sequence-specific antitumor alkylating agent DNA damage from cells treated in culture and from a patient.
Detection of sequence-specific DNA damage induced by antitumor alkylating agents might provide a mechanism for detecting and discriminating damage specific to one or more of these drugs. Using repetitive primer-extension and human alphoid DNA as a substrate, lesions specific for an activated form of cyclophosphamide, 4-hydroperoxycyclophosphamide, were detected at 32 of 33 guanines within a 200-base pair region in DNA from cells treated in culture. There was a marked variation in lesion site intensity among affected guanines. For instance, guanines flanked by cytosine were weak sites of 4-hydroperoxycyclophosphamide-induced damage. Damage at bases other than guanine induced by cisplatin, UV irradiation, and adozelesin were compared to drug-DNA lesions induced by 4-hydroperoxycyclophosphamide. Using this method it was possible to detect, and at some sites distinguish, between cyclophosphamide- and cisplatin-induced DNA damage within WBC DNA from a patient treated with both agents. There was a different damage pattern for DNA derived from cells treated in culture compared to DNA derived from the patient sample.
Bubley
G J
GJ
Division of Hematology/Oncology, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215.
Ogata
G K
GK
Dupuis
N P
NP
Teicher
B A
BA
D001483:Base Sequence / Q000187:drug effects / Q000528:radiation effects; D001572:Benzofurans; D002945:Cisplatin / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D053138:Cyclohexenes; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage / Q000235:genetics*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured
D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D004273:DNA, Neoplasm; D000080890:Duocarmycins; D007211:Indoles; C060090:adozelesin; D003520:Cyclophosphamide; D002945:Cisplatin; C011272:perfosfamide