ATP chemosensitivity testing of new antitumor duplex drugs linking 3`-C-ethynylycytidine (ECyd) and 2´-deoxy-5-fluorouridine (5-FdU) in comparison to standard cytostatica and combinations thereof.
BACKGROUND
2´-Deoxy-5-fluorouridylyl-(5´-5´)-3´-C-ethynylcytidine [5-FdU(5´-5´)ECyd] and 3´-C-ethynylcytidinylyl-(5´->1-O)-2-O-octadecyl-sn-glycerylyl-(3-Ο->5´)-2´-deoxy-5-fluorouridine [ECyd-lipid-5-FdU] are antitumor active duplex drugs and these heterodinucleoside phosphate analogues could be cleaved in vivo by wide-spread phosphodiesterases into different antitumor active antimetabolites.


METHODS
We cultured breast MCF-7, MDA-MB-231 and ovarian OVCAR-29 and OAW-42 cancer cell lines and used the luminometric measuring of the ATP tumor chemosensitivity assay to assess the in vitro activity of 5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU in comparison to standard single cytostatic agents and combinations thereof currently used in anticancer therapies. To allow comparison between samples and different regimens IndexSUM was determined based on the percentage tumor cell growth inhibition at each test drug concentration. Additionally, the cytostatic efficacy of 5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU was evaluated at a minimum of five concentrations at 10 fold dilutions using 60 human tumor cell lines including ovarian and breast cancer cell lines from the National Cancer Institute (USA).


RESULTS
5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU have a high cytostatic efficacy reaching 50% tumor cell growth inhibition at concentrations ranging between nano- and micomolar. IndexSum values for broad range efficacy in MCF-7 breast cancer cells were comparable to values obtained for standard drug combinations. Higher cytostatic efficacy was observed in MDA-MB-231 cells.


CONCLUSIONS
The duplex drugs 5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU represent potential new chemotherapeutic drugs for breast and ovarian cancer cells which are comparable to currently used drug combinations and more potent in comparison to some monocytostatica used in cancer therapy.
Schott
Sarah
S
Medical School, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, 69115, Germany.
Wallwiener
Markus
M
Kootz
Beate
B
Seeger
Harald
H
Fehm
Tanja
T
Neubauer
Hans
H
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D012015:Reference Standards
C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000970:Antineoplastic Agents; C061519:5-formyl-2'-deoxyuridine; D003562:Cytidine; D000255:Adenosine Triphosphate; D003857:Deoxyuridine