Regulating the fate of mRNA: The control of cellular iron metabolism

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

The heme-heme oxygenase system has recently been recognized to possess important regulatory properties. It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection, apoptosis, and inflammation. Heme functions as a double-edged sword. In moderate quantities and bound to protein, it forms an essential element for various biological processes, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. The effect of this free heme on the vascular system is determined by extracellular factors, such as hemoglobin/heme-binding proteins, haptoglobin, albumin, and hemopexin, and intracellular factors, including heme oxygenases and ferritin. Heme oxygenase (HO) enzyme activity results in the degradation of heme and the production of iron, carbon monoxide, and biliverdin. All these heme-degradation products are potentially toxic, but may also provide strong cytoprotection, depending on the generated amounts and the microenvironment. Pre-induction of HO activity has been demonstrated to ameliorate inflammation and mediate potent resistance to oxidative injury. A better understanding of the complex heme-heme

S S Bottomley

Papers

Pathophysiology of heme synthesis.

Secondary iron overload disorders.