TY - JOUR
T1 - Theophylline reversal of alkylator-induced replicon initiation inhibition
T2 - no correlation with DDP-induced cytotoxicity
AU - Ducore, Jonathan M.
AU - Rosenstein, Barry S.
N1 - Funding Information:
This work supported in part by PHS Grant 1-R23-CA35156-01. Dr. Ducore is a Junior Faculty Clinical Fellow of the American Cancer Society.
PY - 1984/10
Y1 - 1984/10
N2 - The synergistic cytotoxic activity exhibited by bifunctional alkylating agents in the presence of methylxanthines has been associated with methylxanthine-induced reversal of alkylator-induced DNA replicon initiation inhibition. This has also beenseen with methylxanthines and ionizing irradiation. Methylxanthines do not appear exacerbate drug or ionizing radiation-induced damage. We report here a situation in which methylxanthine-induced reversal of DNA replicon initiation inhibition is not associated with increased cytotoxicity of the alkylator. Murine L1210 leukemia cells were assayed for cytotoxicity following treatment with either l-PAM or cis-DDP in the presence or absence of theophylline. Theophylline increased the cytotoxicity seen after l-PAM treatment but failed to increase the cis-DDP induced cytotoxicity. Analysis of pulse-labeled DNA on alkaline sucrose gradients revealed the expected decrease in DNA replicton initiation in L1210 cells treated with either l-PAM or cis-DDP. Theophylline had no effect on replicon initiation in untreated cells. Theophylline reversed the replicon initiation inhibition in cells treated with either l-PAM or cis-DDP. The reason for the apparent lack of added toxicity of the replicon initiation inhibition reversal in L1210 cells treated with theophylline and DDP is unknown.
AB - The synergistic cytotoxic activity exhibited by bifunctional alkylating agents in the presence of methylxanthines has been associated with methylxanthine-induced reversal of alkylator-induced DNA replicon initiation inhibition. This has also beenseen with methylxanthines and ionizing irradiation. Methylxanthines do not appear exacerbate drug or ionizing radiation-induced damage. We report here a situation in which methylxanthine-induced reversal of DNA replicon initiation inhibition is not associated with increased cytotoxicity of the alkylator. Murine L1210 leukemia cells were assayed for cytotoxicity following treatment with either l-PAM or cis-DDP in the presence or absence of theophylline. Theophylline increased the cytotoxicity seen after l-PAM treatment but failed to increase the cis-DDP induced cytotoxicity. Analysis of pulse-labeled DNA on alkaline sucrose gradients revealed the expected decrease in DNA replicton initiation in L1210 cells treated with either l-PAM or cis-DDP. Theophylline had no effect on replicon initiation in untreated cells. Theophylline reversed the replicon initiation inhibition in cells treated with either l-PAM or cis-DDP. The reason for the apparent lack of added toxicity of the replicon initiation inhibition reversal in L1210 cells treated with theophylline and DDP is unknown.
UR - http://www.scopus.com/inward/record.url?scp=0021136173&partnerID=8YFLogxK
U2 - 10.1016/0165-7992(84)90022-8
DO - 10.1016/0165-7992(84)90022-8
M3 - Article
C2 - 6541756
AN - SCOPUS:0021136173
SN - 0165-7992
VL - 141
SP - 117
EP - 121
JO - Mutation Research Letters
JF - Mutation Research Letters
IS - 2
ER -