Potentiation of radioresponse by polymer-drug conjugates.
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.
Ke
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Department of Diagnostic Radiology, Box 59, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Milas
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Charnsangavej
C
C
Wallace
S
S
Li
C
C
D000818:Animals; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000532:radiotherapy; D011108:Polymers; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D011108:Polymers; D011838:Radiation-Sensitizing Agents