Platinum-acridinylthiourea conjugates show cell line-specific cytotoxic enhancement in H460 lung carcinoma cells compared to cisplatin.
Recently, we reported a new class of DNA-targeted hybrid platinum-acridine agents. The parent intercalator, ACRAMTU, a 9-aminoacridine derivative, intercalates into the minor groove of DNA, causing the corresponding prototypical conjugate, PT-ACRAMTU (type I/n=2), to form DNA adducts dissimilar to traditional platinum drugs. Both these agents show cytotoxic activity in leukemic and ovarian cancer cells. Following the use of clonogenic survival assays, we report on the cytotoxic effects of ACRAMTU, PT-ACRAMTU, and three PT-ACRAMTU derivatives, on additional cell lines including colon (RKO), lung (H460), and cisplatin-sensitive (A2780) and cisplatin-resistant (A2780/CP) ovarian cells. While a dose-dependent effect was observed with both ACRAMTU and PT-ACRAMTU, an enhanced cytotoxic effect was seen with PT-ACRAMTU in all cell lines. PT-ACRAMTU appeared to have a similar IC50 value to cisplatin except in H460 lung cancer cells in which PT-ACRAMTU had a twofold lower IC50 value. PT-ACRAMTU appeared to act in a time-dependent manner. In H460 cells the IC50 value of PT-ACRAMTU was 235-fold higher following a 1-h incubation than following a 24-h incubation (0.27 microM), while following an 8-h incubation the IC50 value was 0.41 microM. Three derivatives of PT-ACRAMTU were also tested. A tetraalkylated derivative, type II/n=2, generated the highest IC50 values in all cell lines, while the trialkylated derivative, type III/n=2, generated IC50 values similar to its isomer, PT-ACRAMTU. PT-ACRAMTU with an added CH2 group in the thiourea linker (type I/n=3) showed IC50 values similar to the type I/n=2 prototype in H460 lung cells. An apoptotic response to PT-ACRAMTU appeared to be generated in H460 cells as evidenced by DNA laddering. These results suggest that type I/n=2 and type I/n=3 may be promising agents for the treatment of lung cancer and should be pursued in animal models.
Hess
Suzanne M
SM
Department of Radiation Oncology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
Mounce
Amanda M
AM
Sequeira
Russel C
RC
Augustus
Todd M
TM
Ackley
Margaret C
MC
Bierbach
Ulrich
U
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D018736:DNA Adducts / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D010984:Platinum / Q000627:therapeutic use*; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use
C471910:1-(2-(acridin-9-ylamino)ethyl)-1,3-dimethylthiourea; D018736:DNA Adducts; D010984:Platinum; D014508:Urea; D002945:Cisplatin