Tumor irradiation enhances the tumor-specific distribution of poly(L-glutamic acid)-conjugated paclitaxel and its antitumor efficacy.

Abstract

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.

• Authors: C Li, S Ke, Q P Wu, W Tansey, N Hunter, L M Buchmiller, L Milas, C Charnsangavej, S Wallace
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 7 Pg. 2829-34 (Jul 2000) ISSN: 1078-0432 [Print] United States
• PMID: 10914731 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Endothelial Growth Factors
• Lymphokines
• Taxoids
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Polyglutamic Acid
• Paclitaxel
• paclitaxel poliglumex

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Biological Transport
• Capillary Permeability
• Combined Modality Therapy
• Endothelial Growth Factors (blood)
• Female
• Lymphokines (blood)
• Mice
• Mice, Inbred C3H
• Ovarian Neoplasms (blood supply, drug therapy, radiotherapy)
• Paclitaxel (analogs & derivatives, pharmacokinetics, therapeutic use)
• Polyglutamic Acid (pharmacokinetics, therapeutic use)
• Taxoids
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors