Posttreatment exposure to camptothecin enhances the lethal effects of x-rays on radioresistant human malignant melanoma cells.
Little is known about the molecular mechanisms responsible for the survival recovery process(es) (known as potentially lethal damage repair), which occurs in mammalian cells following ionizing radiation. Previously, we presented data indicating a role for the DNA unwinding enzyme, topoisomerase I, in DNA repair. We now demonstrate that camptothecin, a specific inhibitor of topoisomerase I, causes dramatic radiosensitization of an extremely resistant human melanoma (U1-Mel) cell line. Camptothecin radiosensitized U1-Mel cells when it was administered either during or immediately following x-irradiation. U1-Mel cells were optimally radiosensitized with 4 microM camptothecin for a period of 4-6 hrs after x-irradiation. Enhanced cell killing by camptothecin was proportional to the initial extent of damage created by x-irradiation; the higher the dose of ionizing radiation, the greater the radiosensitization. The apparent synergy observed with camptothecin and x-rays was irreversible; camptothecin-treated U1-Mel cells were not able to carry out PLDR in a 48 hr period after the drug was removed. We hypothesize that the administration of camptothecin causes lesion modification through a topoisomerase I-mediated mechanism. These data support a role for topoisomerase I in DNA repair and indicate that camptothecin, or more effective derivatives, may have clinical use.
Boothman
D A
DA
University of Michigan Medical Center, Ann Arbor 48109.
Wang
M
M
Schea
R A
RA
Burrows
H L
HL
Strickfaden
S
S
Owens
J K
JK
D002166:Camptothecin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D004247:DNA / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000473:pathology* / Q000532:radiotherapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014965:X-Rays
D011838:Radiation-Sensitizing Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; D002166:Camptothecin