Potentiation of radioresponse by polymer-drug conjugates.

Abstract

Although combined chemotherapy and radiotherapy has produced significantly improved response and survival rates among cancer patients, there is still a compelling need to establish the most effective way to deliver these agents. We hypothesize that the radiosensitizing effect of a chemotherapeutic agent can be further enhanced if the drug is delivered at an optimal concentration and is maintained in the tumor for a prolonged period. Using a water-soluble poly(L-glutamic acid)-conjugated paclitaxel (PG-TXL) as a model compound, we investigated whether paclitaxel delivered by means of polymeric carrier could increase the tumor's response to radiation. Mice bearing 8-mm syngeneic ovarian carcinoma OCa-1 tumors implanted intramuscularly were treated with i.v. injected PG-TXL alone or in combination with single doses of local radiation. The enhancement factors at 24 h interval, as measured by incremental tumor growth delay compared with radiation alone, ranged from 2.48 to 4.28. The values varied as a function of radiation dose. The enhancement of radioresponse is also a function of time interval between injection of PG-TXL and tumor irradiation. The enhancement factor increased with decreasing interval, suggesting that radiation may in turn mediate the sensitivity of tumor toward PG-TXL. Thus, the mechanism of PG-TXL's radiopotentiation activity is probably multifactorial. Remarkably, while combined radiation and TXL produced additive or even sub-additive interaction when radiation preceded TXL injection, combined radiation and PG-TXL produced synergistic interaction in a mammary MCa-4 tumor model. Radiation significantly increased tumor uptake of PG-TXL, suggesting a potential role of radiation-modulated antitumor activity of polymeric drugs. Our data support a treatment strategy combining radiation and polymeric chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.

• Authors: S Ke, L Milas, C Charnsangavej, S Wallace, C Li
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 74 Issue 1-3 Pg. 237-42 (Jul 06 2001) ISSN: 0168-3659 [Print] Netherlands
• PMID: 11489500 (Publication Type: 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

• Polymers
• Radiation-Sensitizing Agents

Topics

• Animals
• Drug Delivery Systems
• Female
• Flow Cytometry
• Mice
• Models, Biological
• Ovarian Neoplasms (radiotherapy)
• Polymers
• Radiation-Sensitizing Agents (administration & dosage, pharmacokinetics, pharmacology)
• Tissue Distribution
• Tumor Cells, Cultured