TY - JOUR
T1 - Concentration and timing dependence of lethality enhancement between topotecan, a topoisomerase I inhibitor, and ionizing radiation
AU - Lamond, John P.
AU - Wang, Meizhi
AU - Kinsella, Timothy J.
AU - Boothman, David A.
N1 - Funding Information:
Reprint requests to: David A. Boothman, Ph.D., Department of Human Oncology, K4/626, Clinical Science Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, WI 53792. Acknowledgemenrs-J.P.L. is a recipient of an ASTRO Fellowship, RSNA Resident Research Grant, and Physician Sci-
PY - 1996/9/1
Y1 - 1996/9/1
N2 - Purpose: Topotecan (TPT) is a water-soluble Topoisomerase I (Topo I) inhibitor with reported antineoplastic activity against a variety of solid tumors (including nonsmall cell lung, small cell lung, ovarian, breast, esophageal, and head and neck primaries) and leukemias. We sought to determine: (a) if TPT enhanced the lethal effects of ionizing radiation; and (b) the biological and biochemical characteristics of the enhancement. Methods and Materials: Quiescent human radioresistant melanoma (U1-Mel) cells were x-irradiated (1-12 Gy) and exposed to various TPT concentrations (0.1- 300 μM) either before (for 4 h), during, or after (for 4 h) radiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of TPT on radiation-related potential lethal damage repair (PLDR) and sublethal damage repair (SLDR) were measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo 1 complexes. Results: Enhanced radiation lethality by TPT was observed using quiescent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 4 μM TPT was 1.6 at 10% survival. The effect was: (a) dependent on drug concentration, with lethality enhancement and minimal drug lethality alone in the 2-10 μM range for a 4 h posttreatment; (b) dependent on timing, with enhancement observed only when drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR and SLDR. Exposure to TPT during or after radiation substantially elevated DNA-Topo I complexes (four- to tenfold) over control levels and complex formation correlated to some degree with loss of survival. Conclusions: TPT enhanced radiation lethality in vitro at low drug concentrations that are clinically feasible. The rationale and design of an ongoing Phase I that which utilizes concurrent TPT and radiation is discussed.
AB - Purpose: Topotecan (TPT) is a water-soluble Topoisomerase I (Topo I) inhibitor with reported antineoplastic activity against a variety of solid tumors (including nonsmall cell lung, small cell lung, ovarian, breast, esophageal, and head and neck primaries) and leukemias. We sought to determine: (a) if TPT enhanced the lethal effects of ionizing radiation; and (b) the biological and biochemical characteristics of the enhancement. Methods and Materials: Quiescent human radioresistant melanoma (U1-Mel) cells were x-irradiated (1-12 Gy) and exposed to various TPT concentrations (0.1- 300 μM) either before (for 4 h), during, or after (for 4 h) radiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of TPT on radiation-related potential lethal damage repair (PLDR) and sublethal damage repair (SLDR) were measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo 1 complexes. Results: Enhanced radiation lethality by TPT was observed using quiescent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 4 μM TPT was 1.6 at 10% survival. The effect was: (a) dependent on drug concentration, with lethality enhancement and minimal drug lethality alone in the 2-10 μM range for a 4 h posttreatment; (b) dependent on timing, with enhancement observed only when drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR and SLDR. Exposure to TPT during or after radiation substantially elevated DNA-Topo I complexes (four- to tenfold) over control levels and complex formation correlated to some degree with loss of survival. Conclusions: TPT enhanced radiation lethality in vitro at low drug concentrations that are clinically feasible. The rationale and design of an ongoing Phase I that which utilizes concurrent TPT and radiation is discussed.
KW - DNA repair
KW - DNA-Topo I complexes
KW - PLDR
KW - SLDR
KW - Topoisomerase I
UR - http://www.scopus.com/inward/record.url?scp=0030248750&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030248750&partnerID=8YFLogxK
U2 - 10.1016/S0360-3016(96)00328-8
DO - 10.1016/S0360-3016(96)00328-8
M3 - Article
C2 - 8892461
AN - SCOPUS:0030248750
SN - 0360-3016
VL - 36
SP - 361
EP - 368
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 2
ER -