Clinical and biological studies of estramustine phosphate as a novel radiation sensitizer.
OBJECTIVE
Estramustine phosphate (EMP), a nor-nitrogen mustard carbamate derivative of estradiol-17 beta-phosphate, causes G2/M phase arrest in treated cells through its specific binding to microtubule associated proteins. Since cells in the G2/M phase are the most radiosensitive, cell culture experiments were performed to determine whether EMP would enhance the radiosensitivity of related human tumor cells. Based on the cell culture findings and well known pharmacokinetic data in humans, a Phase II prospective study of concomitant radiotherapy (RT) and EMP plus Velban for locally advanced carcinoma of the prostate was carried out.


METHODS
Three established human tumor cells, DU-145 cells (prostate), MCF-7 cells (breast), and U-251 cells (malignant glioma), were used to determine cell survival curves with and without the drug. Flow cytometry was used to obtain the cell cycle distribution of cells that were exposed to the drug for periods of 1 day to 1 week. Patients with locally advanced prostate cancer (Stages B2, C, D1) were entered into the Phase II study. All patients received a total tumor dose of 65-70 Gy over 7 weeks. Oral EMP was administered daily and Velban was administered weekly, concomitantly during the course of RT.


RESULTS
Radiosensitization was dependent on the exposure time and the drug concentration prior to radiation. No radiosensitization was obtained when cells were exposed to the drug after irradiation. The enhancement ratios varied from 1.3-1.6 at the 10% survival level. All patients who received the combined RT and EMP plus Velban achieved complete response (n = 27). The rate of PSA (prostate specific antigen) reduction was very prompt compared to that of the RT alone group. There was not disproportionately enhanced side effects for the combined regimen.


CONCLUSIONS
EMP enhances radiation induced cytotoxicity in several human tumor cells in culture. The effect is most significant after prolonged exposure to the drug before irradiation. Documented G2/M phase cell cycle block by EMP is the likely mechanism of radiosensitization. The preliminary clinical findings with the combined RT and drugs are highly encouraging.
Kim
J H
JH
Henry Ford Hospital, Department of Radiation Oncology, Detroit, MI 48202.
Khil
M S
MS
Kim
S H
SH
Ryu
S
S
Gabel
M
M
D000230:Adenocarcinoma / Q000532:radiotherapy*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004961:Estramustine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D011838:Radiation-Sensitizing Agents; D004961:Estramustine