Biomodulatory approaches to photodynamic therapy for solid tumors

Abstract

Photodynamic Therapy (PDT) uses a photosensitizing drug in combination with visible light to kill cancer cells. PDT has an advantage over surgery or ionizing radiation because PDT can eliminate tumors without causing fibrosis or scarring. Disadvantages include the dual need for drug and light, and a generally lower efficacy for PDT vs. surgery. This minireview describes basic principles of PDT, photosensitizers available, and aspects of tumor biology that may provide further opportunities for treatment optimization. An emerging biomodulatory approach, using methotrexate or Vitamin D in combination with aminolevulinate-based PDT, is described. Finally, current clinical uses of PDT for solid malignancies are reviewed.

Fig. 1. Photodynamic therapy with ALA

Pretreatment with an agent such as Vit D (step 1) leads to increased activity of the heme synthesis pathway. When ALA is given (step 2), more PpIX is produced. Light exposure (step 3) excites PpIX, generates free radicals, and initiates apoptosis (step 4). ALA, 5-aminolevulinic acid. Enzymes of the heme pathway: PBGD, porphobilinogen deaminase; CPO, coproporphyrinogen oxidase; FC, ferrochelatase. PpIX, protoporphyrin IX.

Figure 2. Examples of the biomodulatory effects of a differentiation-promoting agent (1,25 dihydroxy-vitamin D3; calcitriol) upon a solid tumor

The A431 squamous cell carcinoma line was implanted subcutaneously in nude mice. Mice were preconditioned with daily i.p. injections of calcitriol (1 μg/kg body weight) for 3 days, and on the 4th day, ALA was administered for 4 hr prior to tumor harvest (A–C) or illumination with 635 nm light (D). Compare to inert saline controls (A–C), the calcitriol preconditioned tumors (A' – C') exhibited higher PpIX levels by confocal microscopy (A, A') in sections with equal cellularity (B, B'), and also showed stronger staining of a differentiation-associated molecule, ECadherin (C, C'). Scale bars, 50 μm. At various times after 635 nm illumination, histological H&E staining revealed significantly more cell death in the calcitriol-pretreated tumors (D). Scale bar, 250 μm. Adapted from ref. [28], with permission.