SN-38, a metabolite of the camptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation in human colon adenocarcinoma cells grown as spheroids.
OBJECTIVE
CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is anew semisynthesized derivative of camptothecin. SN-38 (7-ethyl-10-hydroxycamptothecin), a metabolite of CPT-11, plays a key role in the action of CPT-11.


METHODS
To determine whether SN-38 potentiates the cytotoxic effect of radiation, we investigated the interaction of SN-38 and radiation in vitro in monolayer cultures and multicellular spheroids of HT-29 human colon adenocarcinoma cells.


RESULTS
HT-29 spheroids were more resistant to both SN-38 and irradiation than monolayer cells. SN-38 at a concentration of 2.5 microg/ml, which by itself was not cytotoxic, greatly increased the lethal effects of radiation in spheroids, but not in monolayer cultures. Exposure to SN-38 following irradiation inhibited the potentially lethal damage repair (PLDR) in spheroids. It is suggested that the mechanism of the radiosensitization by SN-38 is due to the PLDR inhibition.


CONCLUSIONS
These results indicate that CPT-11 may play a role as radiosensitizer and that a combination of CPT-11 and irradiation could prove to be a particularly effective strategy with which to treat human colon adenocarcinoma.
Omura
M
M
Department of Radiology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan.
Torigoe
S
S
Kubota
N
N
D000230:Adenocarcinoma / Q000532:radiotherapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D006801:Humans; D000077146:Irinotecan; D011829:Radiation Dosage; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000528:radiation effects*
D011838:Radiation-Sensitizing Agents; D000077146:Irinotecan; D002166:Camptothecin