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¹ Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano" and Istituto di Endocrinologia ed Oncologia Sperimentale/Consiglio Nazionale delle Ricerche, Università di Napoli Federico II, Naples, Italy; ² Dipartimento di Farmacologia, Università di Milano, Milan, Italy; and ³ Dipartimento di Biologia, Università di Padova, Padua, Italy

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

We compared the effects of monotherapy (photodynamic therapy or chemotherapy) versus combination therapy (photodynamic therapy plus a specific drug) on the non–small cell lung cancer cell line H1299. Our aim was to evaluate whether the additive/synergistic effects of combination treatment were such that the cytostatic dose could be reduced without affecting treatment efficacy. Photodynamic therapy was done by irradiating Photofrin-preloaded H1299 p53/p16-null cells with a halogen lamp equipped with a bandpass filter. The cytotoxic drugs used were cis-diammine-dichloroplatinum [II] (CDDP or cisplatin) and 2',2'-difluoro-2'-deoxycytidine (gemcitabine). Various treatment combinations yielded therapeutic effects (trypan blue dye exclusion test) ranging from additive to clearly synergistic, the most effective being a combination of photodynamic therapy and CDDP. To gain insight into the cellular response mechanisms underlying favorable outcomes, we analyzed the H1299 cell cycle profiles and the expression patterns of several key proteins after monotherapy. In our conditions, we found that photodynamic therapy with Photofrin targeted G₀-G₁ cells, thereby causing cells to accumulate in S phase. In contrast, low-dose CDDP killed cells in S phase, thereby causing an accumulation of G₀-G₁ cells (and increased p21 expression). Like photodynamic therapy, low-dose gemcitabine targeted G₀-G₁ cells, which caused a massive accumulation of cells in S phase (and increased cyclin A expression). Although we observed therapeutic reinforcement with both drugs and photodynamic therapy, reinforcement was more pronounced when the drug (CDDP) and photodynamic therapy exert disjointed phase-related cytotoxic activity. Thus, if photodynamic therapy is appropriately tuned, the dose of the cytostatic drug can be reduced without compromising the therapeutic response. [Mol Cancer Ther 2006;5(3):776–85]

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Note: E. Crescenzi and A. Chiaviello contributed equally to this work.

Received 10/14/05; revised 12/23/05; accepted 1/12/06.

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