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Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," University of Naples, Federico II, Naples, Italy

Requests for Reprints: Giuseppe Palumbo, Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," University of Naples, Federico II, Via S. Pansini 5, 80131 Naples, Italy. Phone: 39-81-7463249; Fax: 39-81-7701016. E-mail: palumbo{at}unina.it

Objective: We investigated the effects of photodynamic therapy (PDT) combined with low-dose chemotherapy on breast cancer cells. Photodynamic treatment was administered by irradiating indocyanine green-preloaded MCF-7 cells with an IR diode laser source at 805 nm; cisplatin was used for chemotherapy. Methods: The dose-response phenomena associated with the two treatments administered individually and together were evaluated with the following tests: trypan blue dye exclusion, 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic survival, thymidine and methionine incorporation, and insulin-dependent and insulin-independent glucose transport. Results: Viability and metabolic data demonstrated mutual reinforcement of therapeutic efficacy. However, isobolographic analysis of quantal and variable data indicated that reinforcement was additive according to trypan blue data and synergistic according to MTT data. To investigate the molecular mechanisms underlying alterations in cell proliferation and apoptosis, we evaluated (by Western blotting) the expression of proteins Bcl-2, Bax, Bcl-X_L, p21, p53, and poly(ADP-ribose) polymerase. Photodynamic treatment caused transient selective destruction of Bcl-2 and up-regulation of Bax. It also induced apoptosis in a limited fraction of cells (10–12%). Flow cytometry data showed that PDT killed mostly G₁-phase cells, whereas cisplatin killed mostly S-phase cells. This disjointed phase-related effect may account for the favorable effects exerted by combined treatment. Conclusions: Our findings imply that low doses of cytostatic drugs may be as effective or even more effective than currently used doses if appropriately combined with PDT.

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Note: E. Crescenzi and L. Varriale contributed equally to this study.

Received 2/ 2/04; revised 3/16/04; accepted 3/22/04.