Tumor irradiation enhances the tumor-specific distribution of poly(L-glutamic acid)-conjugated paclitaxel and its antitumor efficacy.
The poly(L-glutamic acid)-paclitaxel (PG-TXL) conjugate has been shown to exhibit significantly greater antitumor activity than conventionally formulated paclitaxel (TXL) against solid tumors (Li et al., Cancer Res., 58: 2404-2409, 1998). Here we report that local tumor irradiation enhanced the distribution of PG-TXL given 24 h later to ovarian OCa-1 carcinoma implanted i.m. in C3Hf/Kam mice. Radiation significantly increased tumor uptake of PG-TXL and tumor vascular permeability, caused elevation of the serum concentration of vascular endothelial growth factor, and arrested OCa-1 cells in the G1 phase of cell cycle. The enhancement factors, as measured by incremental tumor growth delay compared with PG-TXL alone, ranged from 1.36-4.44. Complete tumor regression was also observed at a higher radiation dose (>10 Gy) and a higher PG-TXL dose (>80 mg equivalentTXL/kg). Furthermore, combined radiation and PG-TXL produced a significantly greater tumor growth delay than treatment with radiation and TXL when both drugs were given at the same equivalent TXL dose of 60 mg/kg 24 h after tumor irradiation (enhancement factors, 4.44 versus 1.50). These data suggest that conjugation of TXL to poly(L-glutamic acid) is necessary for improved response and that the supra-additive effect of combined radiation and PG-TXL therapy is due in part to modulation of the enhanced permeability and retention effect of macromolecules by radiation. We propose a treatment strategy combining radiation and macromolecular chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.
Division of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. cli@di.mdacc.tmc.edu
C
C
Li
S
S
Ke
Q P
QP
Wu
W
W
Tansey
N
N
Hunter
L M
LM
Buchmiller
L
L
Milas
C
C
Charnsangavej
S
S
Wallace
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport; D002199:Capillary Permeability; D003131:Combined Modality Therapy; D016228:Endothelial Growth Factors / Q000097:blood; D005260:Female; D008222:Lymphokines / Q000097:blood; D051379:Mice; D008809:Mice, Inbred C3H; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011099:Polyglutamic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000031:analogs & derivatives; D043823:Taxoids; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex