**4.5.4 PG-PTX facilitates the radiotherapy and chemotherapy**

Preclinical studies in animal tumor models demonstrate the enhanced safety and efficacy of PG-PTX relative to PTX when administered as a single agent or in conjunction with radiation. Studies show that PG-PTX given 24 h before or after radiotherapy enhances tumor growth delay significantly more than PTX. PG-PTX dramatically potentiates tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. PG-PTX increases the therapeutic ratio of radiotherapy more than that previously reported for other taxanes (Milas et al., 2003). PG-PTX not only can produce a much stronger radiopotentiating effect than PTX, the kinetics of its radiopotentiating effect is also different from that of PTX. Delays in the growth of syngeneic murine ovarian OCa-1 tumors grown intramuscularly in C3Hf/Kam mice are used as the treatment end point.

PG-PTX given 24 h before tumor irradiation increases the efcacy of tumor radiation by a factor of more than 4 (Li et al., 2000a). Furthermore, the combination of radiation and PG-PTX can produce a significantly greater tumor growth delay than treatment with radiation and PTX when both drugs are given at the same equivalent PTX dose of 60 mg/kg 24 h after tumor irradiation (enhancement factors, 4.44 versus 1.50) (Li et al., 2000b). When the treatment end point is tumor cure, the enhancement factors are 8.4 and 7.2 of fractionated and single dose radiation, respectively. These values are greater than those produced by other taxanes or by any other chemotherapeutic drugs or radiosensitizer tested so far. PG-PTX may exert its radiopotentiation activity through increased tumor uptake of PG-PTX and sustained release of PTX in the tumor (Li et al., 2000a). To determine whether prior irradiation affects tumor uptake of PG-PTX, PG-[3H] PTX is injected into mice with OCa-1

In another phase I study, PG-PTX is administrated at 70 mg/m2. The mean maximal concentration (Cmax) is 41.2 ± 8.60 μg/mL and the Cmax is reached right after the end of the infusion. The plasma concentration declines with a mean terminal half-life of 15.7 ± 3.17 h. The mean AUC at the MTD is 455 ± 112 μg/h/mL and the mean average systemic plasma clearance is 0.16 ± 0.04 L/h/m2 (Sabbatini et al., 2004). At the MTD, the mean volume of distribution at steady state and during the terminal phase are 1.41 ± 0.28 L/m2 and 3.62 ± 1.13 L/m2, the mean Cmax of unconjugated PTX is 0.21 ± 0.07 μg/mL, the mean Tmax is 0.56 ± 0.18 h, the mean terminal half life is 16.6 ± 7.85 h, and the mean AUC is 3.15 ± 1.16 μg/h/mL. The ratio of the free PTX AUC to the conjugated PTX AUC is 0.7%. The plasma concentration of PTX released from PG-PTX increases largely in proportion to the dose and

Cmax (μg/g) Tmax (h) AUC (μg/h/g) MRT (h)

Total taxanes 72.0 4 4547 51 PTX 4.0 72 345 66

Total taxanes 26.7 1.5 384 23 PTX 22.4 1.5 261 17

Preclinical studies in animal tumor models demonstrate the enhanced safety and efficacy of PG-PTX relative to PTX when administered as a single agent or in conjunction with radiation. Studies show that PG-PTX given 24 h before or after radiotherapy enhances tumor growth delay significantly more than PTX. PG-PTX dramatically potentiates tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. PG-PTX increases the therapeutic ratio of radiotherapy more than that previously reported for other taxanes (Milas et al., 2003). PG-PTX not only can produce a much stronger radiopotentiating effect than PTX, the kinetics of its radiopotentiating effect is also different from that of PTX. Delays in the growth of syngeneic murine ovarian OCa-1 tumors grown intramuscularly in C3Hf/Kam mice are used as the treatment end

PG-PTX given 24 h before tumor irradiation increases the efcacy of tumor radiation by a factor of more than 4 (Li et al., 2000a). Furthermore, the combination of radiation and PG-PTX can produce a significantly greater tumor growth delay than treatment with radiation and PTX when both drugs are given at the same equivalent PTX dose of 60 mg/kg 24 h after tumor irradiation (enhancement factors, 4.44 versus 1.50) (Li et al., 2000b). When the treatment end point is tumor cure, the enhancement factors are 8.4 and 7.2 of fractionated and single dose radiation, respectively. These values are greater than those produced by other taxanes or by any other chemotherapeutic drugs or radiosensitizer tested so far. PG-PTX may exert its radiopotentiation activity through increased tumor uptake of PG-PTX and sustained release of PTX in the tumor (Li et al., 2000a). To determine whether prior irradiation affects tumor uptake of PG-PTX, PG-[3H] PTX is injected into mice with OCa-1

remains similar after repeated administration (Sabbatini et al., 2004).

**4.5.4 PG-PTX facilitates the radiotherapy and chemotherapy** 

Table 3. Preclinical tumor pharmacokinetics.

PG-[3H] PTX

[3H] PTX

point.

tumors 24 h after 15 Gy local irradiation (Li et al., 2000b). The uptake of PG-[3H] PTX in irradiated tumors is 28%−38% higher than that in nonirradiated tumors at different times after PG-[3H] PTX injection, indicating that tumor irradiation can increase the accumulation of PG-PTX in the tumors (Fig. 7).

Anticancer activity in patients who have failed previous chemotherapy, including PTX treatment, is observed with PG-PTX (Sabbatini et al., 2004). Ninety-nine patients in a multicenter phase II study treated with PG-PTX as an i.v. infusion approximately 10 min at a dose of 175 mg/m2 on day 1 of each 3-week cycle have received at least one cycle of treatment. Response rates categorized by platinum sensitivity are shown in Table 4.

Fig. 7. Effects of combined radiation and PG-PTX and radiation and PTX on the growth of OCa-1 tumors in mice.


Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease.

Table 4. Response by Platinum Sensitivity.
