Schedule-dependent interaction between Doxorubicin and mTHPC-mediated photodynamic therapy in murine hepatoma in vitro and in vivo.

PURPOSE: To evaluate cytotoxic and antitumor effects of a conventional anticancer drug Doxorubicin (Dox) and photodynamic therapy (PDT) mediated by a promising photosensitizer of second generation meta-tetra (3-hydroxyphenyl)-chlorin (mTHPC) in combination. METHODS: Murine hepatoma MH-22A was used for investigation in vitro and in vivo. In vitro, the cells were incubated with 0.15 microg/ml mTHPC for 18 h and exposed to light from LED array (lambda = 660+/-20 nm) at 0.6-2.4 kJ/m2. 0.05-0.2 microg/ml Dox was administered either 24 h prior to or immediately after light exposure (Dox-->PDT or PDT + Dox, respectively). The cytotoxicity was tested by staining with crystal violet. The character of the combined effect was assessed by multiple regression analysis. In vivo, the antitumor activity was estimated by monitoring the tumor volume over time, in mice transplanted subcutaneously with MH-22A and treated with Dox and/or PDT. For PDT, mice were exposed to light from diode laser (lambda = 650+/-2 nm) at 12 kJ/m2 following 24 h after administration of 0.15 mg/kg mTHPC. A 3 mg/kg Dox was administered either within 15 min prior to mTHPC or within 15 min after light exposure (Dox-->PDT or PDT + Dox, respectively). RESULTS: Both in vitro and in vivo, the combination of mTHPC-mediated PDT and Dox was evaluated to be more effective than each treatment alone. In vitro, the difference between cell viability curves after photodynamic treatment as a single modality and after combination of photodynamic treatment with Dox was statistically significant under most of the applied conditions (P < or = 0.02). In the case of PDT + Dox, the combination had an additive character, and the sequence Dox-->PDT caused a sub-additive interaction. In vivo, both regimens of combination were more effective in inhibiting tumor growth than any single treatment (P < 0.09). The antitumor activity of PDT + Dox regimen was more prominent than that of Dox-->PDT; however, significance of the difference was not high (P = 0.08). CONCLUSIONS: These results indicate that Dox potentiates therapeutic efficacy of mTHPC-mediated PDT and vice versa, and the degree of potentiation is influenced by the combination schedule: administration of Dox immediately after light exposure is preferable to administration of Dox at 24 h prior to light exposure.

Effects of photodynamic therapy in combination with Adriamycin.

The combination of photodynamic therapy (PDT) and Adriamycin (ADM) was studied in the animal model system. Photohem (PH) was used as a photosensitizer. Mice bearing carcinoma epidermoides LL of the lung received PH once at a dose 10 mg/kg and after 24 h ADM was injected i.p. at a dose 3 mg/kg and tumors were illuminated with laser light after three different time intervals, 15 min, 3 and 24 h. To evaluate the effect of PDT and PDT combined with ADM the intensity of lipid peroxidation in tumor tissue and in blood serum was determined using the thiobarbituric acid assay. PDT induces an increase of malondialdehyde (MDA) concentration in tumor tissue as well as in blood serum. When PDT is combined with ADM, the MDA level in tumor tissue is similar to the level of this product as in the PDT alone. No enhancement of the efficiency of the combined treatment was observed at these experimental conditions. This is also confirmed by the tumor growth dynamics, survival time of animals and flow cytometric DNA analysis of tumor cells. For the successful combination of PDT with chemotherapy it is suggested to apply the drugs at the regimen which will allow to avoid the interaction between two agents since the ground state interaction between PH and ADM is stated spectroscopically. It should lead to the conclusion that the sequence of the combination of two treatment modalities is an important factor for synergistic effect.

Embryotoxicity and teratogenicity of some derivatives of chloroethylaminophenylacetic acid.

Embryotoxic and teratogenic properties of Lophenal, Phenalon, Pharanox and Pharanoxi selenate were investigated experimentally. All examined antitumour agents showed embryotoxic effects. Lophenal, Phenalon and Pharanox had teratogenic effects. By modifying the structure of Pharanox with selenium a reduction in teratogenic effect was achieved.