Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability.
OBJECTIVE
Conjugating drugs with polymeric carriers is one way to improve selective delivery to tumors. Poly (L-glutamic acid)-paclitaxel (PG-TXL) is one such conjugate. Compared with paclitaxel, its uptake, tumor retention, and antitumor efficacy are increased. Initial studies showed that PG-TXL given 24 h before or after radiotherapy enhanced tumor growth delay significantly more than paclitaxel. To determine if PG-TXL-induced enhancement is obtained in a more clinically relevant setting, we investigated PG-TXL effects on tumor cure.


METHODS
Mice bearing 7-mm-diameter ovarian carcinomas were treated with PG-TXL at an equivalent paclitaxel dose of 80 mg/kg, single dose or 5 daily fractions of radiation or both PG-TXL and radiation. Treatment endpoint was TCD(50) (radiation dose yielding tumor control in 50% of mice). Acute radioresponse of jejunum, skin, and hair was determined for all treatments.


RESULTS
PG-TXL dramatically improved tumor radioresponse, reducing TCD(50) of single-dose irradiation from 53.9 (52.2-55.5) Gy to 7.5 (4.5-10.7) Gy, an enhancement factor (EF) of 7.2. The drug improved the efficacy of fractionated irradiation even more, reducing the TCD(50) of 66.6 (62.8-90.4) Gy total fractionated dose to only 7.9 (4.3-11.5) Gy, for an EF of 8.4. PG-TXL did not affect normal tissue radioresponse resulting from either single or fractionated irradiation.


CONCLUSIONS
PG-TXL dramatically potentiated tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. To our knowledge, PG-TXL increased the therapeutic ratio of radiotherapy more than that previously reported for other taxanes, thus, PG-TXL has a high potential to improve clinical radiotherapy.
Milas
Luka
L
Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4095, USA. lmilas@mdanderson.org
Mason
Kathryn A
KA
Hunter
Nancy
N
Li
Chun
C
Wallace
Sidney
S
D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy*; D000818:Animals; D003131:Combined Modality Therapy; D016001:Confidence Intervals; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006197:Hair / Q000528:radiation effects; D007262:Infusions, Intravenous; D007579:Jejunal Diseases / Q000209:etiology; D051379:Mice; D008809:Mice, Inbred C3H; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000627:therapeutic use* / Q000031:analogs & derivatives; D011832:Radiation Injuries / Q000209:etiology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011855:Radiodermatitis / Q000209:etiology; D011879:Radiotherapy Dosage; D013047:Specific Pathogen-Free Organisms; D043823:Taxoids
D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex