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.
Li
C
C
Division of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. cli@di.mdacc.tmc.edu
Ke
S
S
Wu
Q P
QP
Tansey
W
W
Hunter
N
N
Buchmiller
L M
LM
Milas
L
L
Charnsangavej
C
C
Wallace
S
S
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