Lack of in vivo cross-resistance with 4'-thio-ara-C against drug-resistant murine P388 and L1210 leukemias.
OBJECTIVE
4'-Thio-β-D-arabinofuranosylcytosine (4'-thio-ara-C), which has shown a broad spectrum of antitumor activity against human tumor systems in mice and is undergoing clinical trials, was evaluated for cross-resistance to seven clinical agents in order to identify potentially useful guides for patient selection for further clinical trials of 4'-thio-ara-C and possible noncross-resistant drug combinations with 4'-thio-ara-C.


METHODS
A drug resistance profile for 4'-thio-ara-C, which was administered intraperitoneally daily for nine consecutive days, was obtained using seven drug-resistant P388 and L1210 leukemias that were implanted intraperitoneally in mice.


RESULTS
Multidrug-resistant P388 leukemias (leukemias resistant to doxorubicin, etoposide, or paclitaxel) exhibited no cross-resistance to 4'-thio-ara-C. Leukemias resistant to camptothecin, cisplatin, and 5-fluorouracil were also not cross-resistant to 4'-thio-ara-C. Only the leukemia resistant to 1-β-D-arabinofuranosylcytosine was cross-resistant to 4'-thio-ara-C.


CONCLUSIONS
The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with 1-β-D-arabinofuranosylcytosine and (2) the lack of cross-resistance seen with 4'-thio-ara-C may contribute to therapeutic synergism when 4'-thio-ara-C is combined with other agents.
Cancer Therapeutics and Immunology Department, Southern Research Institute, Birmingham, AL 35255-5305, USA. waud@southernresearch.org
William R
WR
Waud
Karen S
KS
Gilbert
John A
JA
Secrist
D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D007939:Leukemia L1210 / Q000188:drug therapy*; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D016019:Survival Analysis
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; C411255:4'-thio-arabinofuranosylcytosine