In Vivo Efficacy Evaluations

CT-2103 has been studied in a wide variety of syngeneic and xenogeneic tumour models (Tables 3A and 3B). In all cases it has enhanced efficacy when its maximum tolerated dose (MTD) was compared to that of free paclitaxel administered in Cremophor EL/ethanol. In the mouse strains that were evaluated, the single dose IV or IP MTD for CT-2103 was approximately twice that of paclitaxel administered in Cremophor EL/ethanol [80 mg/kg for paclitaxel in immunocompetent mice (syngeneic models) and 60-70 mg/kg in nu/nu mice respectively compared with 160200 mg/kg in syngeneic mice and 120-150 mg/kg in nu/nu mice for CT-210311'18. An example of the enhanced efficacy of CT-2103 in nude mice bearing the HT-29 human colon cancer is shown in Figure 6.

Figure 6. Effect of CT-2103 vs. Paclitaxel on the Growth of Human HT-29 Colon Carcinomas in Nude Mice

The MTD and tumour growth delay (TGD) in Lewis lung cancer (LL/2) 13 and B16 melanoma syngeneic tumours in female C57BL/6 mice19 after a single IP injection were used to evaluate the biological consistency of CT-2103. In these studies the paclitaxel-equivalent MTD varied between 160 and 240 mg/kg, and the mean ± SD [range] for TGD to 500 mm3 was 3.8 ± 1.8 [range 0.4 - 9.8] days for Lewis lung tumours and 6.2 ± 3.2 [range 1.3 - 13.2] for B16 tumors13,19. The TGD to 500 mm3 for paclitaxel in Cremophor-ethanol at its MTD of 80 mg/kg was 2.0 +/-0.9 [range 0.4-3.5] days (n=16) in mice bearing the LL/2 and 2.0 +/- 1.1 [range 0.7-4.3] days (n=10) in B-16 model (p<0.01 compared to CT-2103 for both models).

Studies in mice using the murine P388 leukemia sub-line selected for mdr1 overexpression and the human colon cancer cell lines that express mdr1 (Table 3B) suggest that intracellular paclitaxel derived from breakdown of CT-2103 is less subject to the multidrug resistance pump than is paclitaxel that enters the cell by diffusion of free paclitaxel20. As has been shown for other polymeric drug conjugates, this is probably due active uptake of the conjugate by tumour cells with breakdown of the PG backbone and release of free paclitaxel at sites distant from the plasma membrane where they cannot be exported by intrinsic plasma membrane pumps.

Studies in mice bearing the OCa-1 ovarian cancer demonstrated that CT-2103 is synergistic when co-administered with gemcitabine, doxorubicin, irinotecan, and carboplatin in a schedule independent manner (data not shown). Preliminary data indicate that it is also a substantially more potent radiosensitiser than paclitaxel in Cremophor EL/ethanol with an enhancement factor in a curative model of multidose radiation reported to be >8.0 compared to approximately 2 for paclitaxel reported in the same model by the same investigator 12,21-24 Of great interest was the observation that unlike free paclitaxel, CT-2103 did not sensitise normal skin or

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