TY - JOUR
T1 - Radiation lethality enhancement with 9-aminocamptothecin
T2 - Comparison to other topoisomerase I inhibitors
AU - Lamond, John P.
AU - Wang, Meizhi
AU - Kinsella, Timothy J.
AU - Boothman, David A.
N1 - Funding Information:
Grant #CA09614. The work was previously supported by American Cancer Society Grant PDT-143, and is currently supported by a Department of Energy grant #DE-FG029 I-ER61256 to D.A.B. This work was also supported by grant CA.50595 to T.J.K. Accepted for publication 4 June 1996.
PY - 1996/9/1
Y1 - 1996/9/1
N2 - Purpose: Preclinical studies have demonstrated differences in potency, solubility, and tumor specific activity among the camptothecin (CPT) analogues. 9-Aminocamptothecin (9-AC) has demonstrated greater potency in animal studies than other clinically available Topoisomerase I (Topo I) inhibitors. We sought to determine: (a) if 9-AC enhanced the lethal effects of ionizing radiation to a greater extent than other Topo I inhibitors; and (b) the biological and biochemical characteristics of the enhancement. Methods and Materials: Quiescent radioresistant human melanoma (U1-Mel) cells were x-irradiated (1-7 Gy) and exposed to various concentrations of 9-AC (0.1 -100 μM), either before (for 4 h), during, or after (for 4 h) irradiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of 9-AC on radiation-related potential lethal damage repair (PLDR) was also measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. Results: Enhancement of radiation lethality was observed using confluent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 10 μM 9-AC was 2.5 at 10% survival. Toxicity from the drug alone was greater than topotecan (TPT), but less than CPT. The radiation synergy effect was: (a) dependent on drug concentration (≤ 2 μM); (b) dependent on timing, with enhancement present only when the drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR. Exposure to 9-AC during or after irradiation substantially elevated the number of DNA- Topo I complexes (four- to tenfold) over control levels and correlated with enhanced loss of survival. Conclusion: 9-Aminocamptothecin enhanced radiation lethality in vitro at low drug concentrations with characteristics similar to other Topo I inhibitors. A greater SER, but greater lethality with the drug alone, was obtained in comparison to TPT. The clinical implications of these findings remain unexplored.
AB - Purpose: Preclinical studies have demonstrated differences in potency, solubility, and tumor specific activity among the camptothecin (CPT) analogues. 9-Aminocamptothecin (9-AC) has demonstrated greater potency in animal studies than other clinically available Topoisomerase I (Topo I) inhibitors. We sought to determine: (a) if 9-AC enhanced the lethal effects of ionizing radiation to a greater extent than other Topo I inhibitors; and (b) the biological and biochemical characteristics of the enhancement. Methods and Materials: Quiescent radioresistant human melanoma (U1-Mel) cells were x-irradiated (1-7 Gy) and exposed to various concentrations of 9-AC (0.1 -100 μM), either before (for 4 h), during, or after (for 4 h) irradiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of 9-AC on radiation-related potential lethal damage repair (PLDR) was also measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. Results: Enhancement of radiation lethality was observed using confluent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 10 μM 9-AC was 2.5 at 10% survival. Toxicity from the drug alone was greater than topotecan (TPT), but less than CPT. The radiation synergy effect was: (a) dependent on drug concentration (≤ 2 μM); (b) dependent on timing, with enhancement present only when the drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR. Exposure to 9-AC during or after irradiation substantially elevated the number of DNA- Topo I complexes (four- to tenfold) over control levels and correlated with enhanced loss of survival. Conclusion: 9-Aminocamptothecin enhanced radiation lethality in vitro at low drug concentrations with characteristics similar to other Topo I inhibitors. A greater SER, but greater lethality with the drug alone, was obtained in comparison to TPT. The clinical implications of these findings remain unexplored.
KW - 9-Aminocamptothecin
KW - DNA repair
KW - PLDR
KW - Topoisomerase I
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U2 - 10.1016/S0360-3016(96)00326-4
DO - 10.1016/S0360-3016(96)00326-4
M3 - Article
C2 - 8892462
AN - SCOPUS:0030249357
SN - 0360-3016
VL - 36
SP - 369
EP - 376
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 2
ER -