Potentiation of ovarian OCa-1 tumor radioresponse by poly (L-glutamic acid)-paclitaxel conjugate

Purpose: It has been shown that paclitaxel (TXL) can strongly enhance tumor cells' sensitivity to radiation. We examined whether the radiosensitizing effect of paclitaxel can be further enhanced when it is delivered systemica lly as a polymer-drug conjugate that provides enhanced tumor uptake and pro longed release of TXL in the turner, Methods and Materials: C3Hf/Kam mice bearing 8-mm murine ovarian OCa-1 tumo rs were treated with i.v.-injected Poly(L-glutamic acid)-paclitaxel (PG-TXL ) at an equivalent TXL dose of 80 mg/kg, followed 23 h later by single dose s of local radiation ranging from 5 to 15 Gy, To determine how long the rad iopotentiation persisted at extended times after PG-TXL administration, mic e with OCa-1 tumors were given i.v. PG-TXL and 4. 23, 48, 72, 120, or 168 h later their tumors were irradiated at a dose of 10 Gy, Antitumor activity was determined by delay in tumor growth, Cell cycle distribution was assaye d using how cytometry. Tumor vascular volume was estimated using Tc-99 m-la beled red blood cells, Results: PG-TXL strongly potentiated the radioresponse of the OCa-1 tumor. The enhancement factors ranged from 2.79 to 4.28, depending on radiation do se, when PG-TXL preceded radiation by 23 h. The enhancement factor derived from radiation close-response curves was as high as 5.13. The radiosensitiz ing effect of PG-TXL was also dependent on the interval between PG-TXL admi nistration and radiation delivery, with greater enhancement been observed w hen the interval was decreased. The percentage of G2/M cells was significan tly increased to 21.4% 38 h after PG-TXL but declined to a preinjection lev el of 14.8% 72 h after PG-TXL. PG-T,YL only moderately increased the tumor vascular volume by 37% 24 h after PG-TXL administration, Conclusion: PG-TXL markedly potentiated response of OCa-1 tumor to radiatio n. When compared to literature data obtained from the same tumor model used here, PG-TXL exhibited stronger radiosensitization effect than TXL, Althou gh its action is possibly mediated by arrest of cells in G2/M phases of cel l cycle and by increased turner blood supply, PG-TXL may exert its radiopot entiation activity through increased tumor uptake of PC-TILL and sustained release of TXL in the tumor, Our results show that conjugation of TXL to a polymer has the potential to further enhance its radiosensitizing activity and that clinical trials of PG-TXL in combination with radiation is warrant ed, (C) 2000 Elsevier Science Inc.