Troxacitabine prodrugs for pancreatic cancer.
Troxacitabine is a cytotoxic deoxycytidine analogue with an unnatural L-configuration, which is activated by deoxycytidine kinase (dCK). The configuration is responsible for differences in the uptake and metabolism of troxacitabine compared to other deoxynucleoside analogues. The main drawback in the use of most nucleoside anticancer agents originates from their hydrophilic nature, which property requires a high and frequent dosage for an intravenous administration. To overcome this problem several troxacitabine prodrugs modified in the aminogroup with a linear aliphatic chain with a higher lipophilicity were developed. To determine whether these prodrugs have an advantage over Troxacitabine pancreatic cancer cell lines were exposed to Troxacitabine and the lipophilic prodrugs. The addition of linear aliphatic chains to troxacitabine increased sensitivity of pancreatic cancer cell lines to the drug > 100-fold, possibly due to a better uptake and retention of the drug.
Adema
A D
AD
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Radi
M
M
Daft
J
J
Narayanasamy
J
J
Hoebe
E K
EK
Alexander
L E
LE
Chu
C K
CK
Peters
G J
GJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004148:Dioxolanes; D011355:Prodrugs; C074908:troxacitabine; D003596:Cytosine