Light-activated, photosensitizer-based therapies have been established as safe modalities of tumour ablation for numerous cancer indications. Two main approaches are available: photodynamic therapy, which results in localized chemical damage in the target lesions, and photothermal therapy, which results in localized thermal damage. Whereas the administration of photosensitizers is a key component of photodynamic therapy, exogenous photothermal contrast agents are not required for photothermal therapy but can enhance the efficiency and efficacy of treatment. Over the past decades, great strides have been made in the development of phototherapeutic drugs and devices as cancer treatments, but key challenges have restricted their widespread clinical use outside of certain dermatological indications. Improvements in the tumour specificity of photosensitizers, achieved through targeting or localized activation, could provide better outcomes with fewer adverse effects, as could combinations with chemotherapies or immunotherapies. In this Review, we provide an overview of the current clinical progress of phototherapies for cancer and discuss the emerging preclinical bioengineering approaches that have the potential to overcome challenges in this area and thus improve the efficiency and utility of such treatments.

Clinical development and potential of photothermal and photodynamic therapies for cancer

Keywords: Photomedicine group Reference LPAS-ARTICLE-1998-003View record in Web of Science Record created on 2007-07-20, modified on 2016-08-08

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1998.tb02521.x

In Vivo Fluorescence Spectroscopy and Imaging for Oncological Applications

BACKGROUND
Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25 years PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light Although several photosensitizers other than ALA-derived protoporphyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis However, no review updating the clinical data has appeared so far

METHODS
A review of recently published data on clinical ALA-based PDT and diagnosis was conducted

RESULTS
Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results However, the modality with present protocols does not, in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs

CONCLUSIONS
Promising results of ALA-based clinical PDT and diagnosis have been obtained The modality has advantages over conventional treatments However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue; improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems Cancer 1997; 79:2282-308 © 1997 American Cancer Society

5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.

The iron(I1) complex of protoporphyrin IX (PpIX)? (heme) is bound to different proteins to form key biomolecules (hemoproteins) such as hemoglobin, myoglobin, cytochromes, catalase, peroxidase and tryptophan pyrrolase. The lives of the cells and of the body as a whole is therefore crucially dependent upon the biosynthesis and metabolism of porphyrins. Almost all types of cells of the human body, with the exception of mature red blood cells, are equipped with a machinery to synthesize heme. In the first step of the heme biosynthetic pathway 5-aminolevulinic acid (ALA) is formed from glycine and succinyl CoA. The synthesis of ALA is regulated by the amount of heme in the cell. The last step in the formation of heme is the incorporation of iron into PpIX and takes place in the mitochondria under the action of the enzyme, ferrochelatase. By adding exogenous ALA, PpIX may accumulate because of the limited capacity of ferrochelatase. Porphobilinogen deaminase (PBGD) is another enzyme that is active in the heme synthesis pathway (catalyzing the formation of uroporphyrinogen from porphobilinogen [PBG]). The activity of this enzyme is higher in some tumors (1-3), while that of ferrochelatase is lower (2-7), so that PpIX accumulates with some degree of selectivity in tumors. Because PpIX is an efficient photosensitizer, ALA has been introduced as a drug for clinical photodynamic therapy (PDT) of cancer (8,9). Photodynamic therapy involves systemic administration of a tumor-localizing photosensitizer and its subsequent activation by light of an appropriate wavelength to create a pho-

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1997.tb08549.x

5‐Aminolevulinic Acid‐Based Photodynamic Therapy: Principles and Experimental Research

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality approved for clinical treatment of several types of cancer and non-oncological disorders. In PDT, a compound with photosensitising properties (photosensitiser, PS) is selectively accumulated in malignant tissues. The subsequent activation of the PS by visible light, preferentially in the red region of the visible spectrum (lambda>or=600 nm), where tissues are more permeable to light, generates reactive oxygen species, mainly singlet oxygen ((1)O(2)), responsible for cytotoxicity of neoplastic cells and tumour regression. There are three main mechanisms described by which (1)O(2) contributes to the destruction of tumours by PDT: direct cellular damage, vascular shutdown and activation of immune response against tumour cells. The advantages of PDT over other conventional cancer treatments are its low systemic toxicity and its ability to selectively destroy tumours accessible to light. Therefore, PDT is being used for the treatment of endoscopically accessible tumours such as lung, bladder, gastrointestinal and gynaecological neoplasms, and also in dermatology for the treatment of non-melanoma skin cancers (basal cell carcinoma) and precancerous diseases (actinic keratosis). Photofrin, ALA and its ester derivatives are the main compounds used in clinical trials, though newer and more efficient PSs are being evaluated nowadays.

Photodynamic therapy of cancer. Basic principles and applications

Human tumor cells of the lines WiDr (adenocarcinoma of the rectosigmoid colon), NHIK 3025 (carcinoma of the cervix), and V79 Chinese hamster fibroblasts were treated with 5-aminolevulinic acid (ALA) and ALA esterified to C1-C3 and C6-C8 chained aliphatic alcohols (ALA-esters). In the human cell lines, esterification of ALA with the long-chain (C6-C8) alcohols was found to reduce 30-150-fold the amount of ALA needed to reach the same level of protoporphyrin IX (PpIX) accumulation as with non-esterified ALA. The long-chained ALA-esters were less efficient in stimulating PpIX formation in V79 cells, i.e., the same amount of PpIX was formed by a 1-2.6-fold lower concentration of long-chained ALA-esters than with ALA. Short-chained ALA-esters (C1-C3) induced 5 to 10 times lower PpIX accumulation than ALA in all of the cell lines. High-performance liquid chromatography and fluorescence microscopic studies indicated that esterification of ALA has neither impact on the fluorescing porphyrin species formed nor impact on their intracellular localization. The PpIX formed from ALA-esters and ALA was found to be equally efficient in sensitizing cells to photoinactivation. The present results indicate that esterified ALAs are new and promising drugs for use in photochemotherapy of cancer.

https://cancerres.aacrjournals.org/content/canres/57/8/1481.full.pdf

Use of 5-aminolevulinic acid esters to improve photodynamic therapy on cells in culture.

Human colon adenocarcinoma cells (WiDr) and Chinese hamster lung fibroblasts cells (V79) were incubated with different concentrations of 5-aminolevulinic acid (ALA), and the production of protoporphyrin IX (PpIX) was studied using several techniques. The amount of PpIX produced per cell increased with increasing ALA concentration according to different kinetics for the 2 cell lines. For both cell lines a cell density dependency of the PpIX synthesis was observed. For saturating ALA concentrations, 2-3 times more PpIX was produced per cell at a density of 5 x 10(4) than at a density of 5 x 10(3) cells/cm2. The photosensitivity of cells appeared to increase even more than the PpIX content, indicating a cooperative effect in inactivation. The PpIX production rate increased with cell size and was about 1.9 times higher for cells in the G2 + M phase than for cells in the G1 phase of the cell cycle. Neither cell size nor cell cycle distribution were significantly dependent on cell density.

Protoporphyrin IX accumulation in cells treated with 5-aminolevulinic acid : Dependence on cell density, cell size and cell cycle

The topoisomerase I (Topo I) inhibitor camptothecin (CPT) has been combined with photodynamic treatment (PDT) in V79 and NHIK 3025 cells. Meso-tetra (N-methyl-4-pyridyl) porphine (TMPyPH2) was used as a photosensitizer. The dye has been shown to localize in granules in the cytoplasm of both cell lines. Some of the granularly located TMPyPH2 is relocated to the cytosol after exposure to a light dose inactivation 70% of the cells. The human NHIK 3025 carcinoma from cervix were more resistant to PDT (D50 approximately equals 0.33 J/cm2) and CPT (D50 approximately equals 320 nM) than Chinese hamster V79 lung fibroblasts (PDT, D20 approximately equals 0.3 J/cm2 and CPT, D20 approximately equals 55 nM). When the cells were treated with CPT for 18 hours before PDT, the combination of treatments led to slight synergistic effects for low CPT concentrations (up to 100 nM in NHIK 3025 cells) and high PDT doses (above 0.15 J/cm2). For higher CPT concentrations and lower PDT doses, the combination of treatment became additive.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Jean Michel Gaullier

Papers

Use of 5-aminolevulinic acid esters to improve photodynamic therapy on cells in culture.

Protoporphyrin IX accumulation in cells treated with 5-aminolevulinic acid : Dependence on cell density, cell size and cell cycle

Combined treatment of photodynamic therapy and the topoisomerase I inhibitor camptothecin in growing V79 and NHIK 3025 cells