Polymeric retinoid prodrug PG-4HPR enhances the radiation response of lung cancer.
To determine whether a polymer-drug conjugate might improve tumor cell kill compared to the corresponding unconjugated agent when used in combination with radiation, we examined the antitumor activity of a water-soluble conjugate of N-(4-hydroxyphenyl) retinamide (4HPR) and poly(L-glutamic acid), PG-4HPR, in lung cancer cells and xenografts. The antiproliferative activity of 4HPR and PG-4HPR in human lung cancer A549 cells was evaluated and the response of the cells to radiation measured by clonogenic assay. Response to irradiation was evaluated by measuring tumor growth delay in nude mice bearing intramuscularly inoculated A549 tumors. Histologic responses were assessed by examination of apoptosis (TUNEL assay) and cell proliferation (Ki67 staining). In vitro, 4HPR and PG-4HPR inhibited the proliferation of A549 cells, with IC50 values of 25.8 microM and >50 microM, respectively, after 24 h of continuous exposure and 6.25 microM and 9.75 microM, respectively, after 120 h. Both agents increased radiosensitivity at an equivalent 4HPR concentration of 10 microM after 5 days of exposure, with enhancement factors of 1.40 and 1.43. In tumor xenografts, intravenous injection of 4HPR or PG-4HPR (30 mg eq. 4HPR/kg) enhanced radiosensitivity by 1.3 and 1.6, respectively, without apparent systemic toxicity. PG-4HPR augmented radiation-induced apoptosis and decreased cellular proliferation in vivo. The radiation response of A549 tumors was greater with PG-4HPR than with 4HPR, which may be attributed to increased delivery of 4HPR to the tumors and enhanced apoptotic response. These results suggest that a polymeric delivery system may be useful for modulating radiosensitivity.
Division of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Guangying
G
Zhu
Xianyi
X
Cao
Joe Y
JY
Chang
Luka
L
Milas
Sidney
S
Wallace
Chun
C
Li
D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D017313:Fenretinide / Q000627:therapeutic use*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011099:Polyglutamic Acid; D011355:Prodrugs / Q000627:therapeutic use
D016588:Anticarcinogenic Agents; D011355:Prodrugs; D017313:Fenretinide; D011099:Polyglutamic Acid