Combination Doxorubicin And Pdt For Ovarian Cancerbenefits Of Hpmacopolymer Conjugation

The efficacy of combining doxorubicin with a photosensitizer in the treatment of a human carcinoma (mesothelioma cell line H-MESO-1) was first reported by Brophy and Keller. [53] In vitro studies with the combination of free doxorubicin and using both dose and effect addition isobolographic analysis demonstrated independent activity, cooperativity, synergy and additivity in their combined toxicity against OVCAR- 3 (Figure 5). [54]

Figure 5. Panel A. The dose-addition isobole analysis for the MTT 72-hour assay and interactions. Columns A and G are the dose-response values for Mce^/light and doxorubicin, respectively. Columns B, C, and D represent the 75% median effective concentration (EDS0) doxorubicin with 25% EDjo Mce^light which was additive (P = 0.62); 50% EDj0 doxorubicin with 50% ED;o Mce^light, which was synergistic (*P = 0.027); and 25% ED50 doxorubicin with 75% EDjo Mce^light (*P = 0.035), which was antagonistic. Panel B. The effect-addition isobole analysis for the MTT 72-hour assay and interactions. Columns A and H are the dose-response values for Mce6 and doxorubicin, respectively. Columns B-G represent various combinations as follows: B = 25% median effective concentration (EDJ0) Mce^light with 50% EDjo doxorubicin, additive; C and F = 50% doxorubicin with 50% EDJ0 Mce,s/light, synergistic (* P < 0.03); D = 50% EDJ0 doxorubicin with 75% EDS0 Mce^/light, additive; E = 75% doxorubicin with 50 EDJ0 Mcee/light, additive; and G = 25% EDS0 adriamycin with 50% EDS0 Mceg/light, synergistic (*P < 0.03). [54]

Figure 5. Panel A. The dose-addition isobole analysis for the MTT 72-hour assay and interactions. Columns A and G are the dose-response values for Mce^/light and doxorubicin, respectively. Columns B, C, and D represent the 75% median effective concentration (EDS0) doxorubicin with 25% EDjo Mce^light which was additive (P = 0.62); 50% EDj0 doxorubicin with 50% ED;o Mce^light, which was synergistic (*P = 0.027); and 25% ED50 doxorubicin with 75% EDjo Mce^light (*P = 0.035), which was antagonistic. Panel B. The effect-addition isobole analysis for the MTT 72-hour assay and interactions. Columns A and H are the dose-response values for Mce6 and doxorubicin, respectively. Columns B-G represent various combinations as follows: B = 25% median effective concentration (EDJ0) Mce^light with 50% EDjo doxorubicin, additive; C and F = 50% doxorubicin with 50% EDJ0 Mce,s/light, synergistic (* P < 0.03); D = 50% EDJ0 doxorubicin with 75% EDS0 Mce^/light, additive; E = 75% doxorubicin with 50 EDJ0 Mcee/light, additive; and G = 25% EDS0 adriamycin with 50% EDS0 Mceg/light, synergistic (*P < 0.03). [54]

For example, the of free doxorubicin combined with the of free Mce6 resulted in a significant synergistic inhibition (27.5 %+ 1.57 of controls) of cell growth compared to approximately 40% inhibition for a twofold concentration of either free drug alone.

In vitro studies using HPMA copolymer-bound doxorubicin and Mce6j in combination, have demonstrated a 10-fold increase in each drug concentration to be equally or more effective than free drug in the models used. These in vitro findings suggest the potential attenuation of combined nonspecific toxicities through HPMA copolymer conjugation. [54] This has been subsequently established in vivo. [33] Using a mouse model of ovarian cancer, HPMA copolymer delivery of doxorubicin or Mce« resulted in a 2-30 fold increase in the free drug equivalent dose delivered without increasing the nonspecific toxicity of either drug. [33] The combination of HPMA copolymer bound doxorubicin and Mce6 resulted in significantly reduced nonspecific toxicity and a notable improvement in tumor cures which could not be obtained by either agent alone. (Figure 6)

Figure 6. Combination chemotherapy and PDT of OVCAR-3 tumors heterotransplanted in nude mice treated with HPMA copolymer-bound anticancer drugs: control (-■-); P-C (12.5 mg/kg, 1.5 mg/kg Mce6 equivalent) with light (-0-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) (-□-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (12.5 mg/kg, 1.5 mg/kg Mces equivalent) without light (-■-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (75 mg/kg, 8.7 mg/kg Mceg equivalent) without light (-□-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (12.5 mg/kg, 1.5 mg/kg Mcej equivalent) with light (-•-); P-C (75 mg/kg, 8.7 mg/kg Mce« equivalent) with light (-A-); and P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (75 mg/kg, 8.7 mg/kg Mce« equivalent) with light (-A-). Bars. SE. P = HPMA copolymer bound. [33]

Figure 6. Combination chemotherapy and PDT of OVCAR-3 tumors heterotransplanted in nude mice treated with HPMA copolymer-bound anticancer drugs: control (-■-); P-C (12.5 mg/kg, 1.5 mg/kg Mce6 equivalent) with light (-0-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) (-□-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (12.5 mg/kg, 1.5 mg/kg Mces equivalent) without light (-■-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (75 mg/kg, 8.7 mg/kg Mceg equivalent) without light (-□-); P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (12.5 mg/kg, 1.5 mg/kg Mcej equivalent) with light (-•-); P-C (75 mg/kg, 8.7 mg/kg Mce« equivalent) with light (-A-); and P-A (30 mg/kg, 2.2 mg/kg Doxorubicin equivalent) plus P-C (75 mg/kg, 8.7 mg/kg Mce« equivalent) with light (-A-). Bars. SE. P = HPMA copolymer bound. [33]

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