James C. Kennedy

Bio: James C. Kennedy is an academic researcher from Queen's University. The author has contributed to research in topics: Protoporphyrin IX & Photodynamic therapy. The author has an hindex of 21, co-authored 46 publications receiving 4124 citations. Previous affiliations of James C. Kennedy include Health Canada & Royal Military College of Canada.

Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience.

Abstract: 5-Aminolaevulinic acid (ALA) is a precursor of protoporphyrin IX (Pp IX) in the biosynthetic pathway for haem. Certain types of cells have a large capacity to synthesize Pp IX when exposed to an adequate concentration of exogenous ALA. Since the conversion of Pp IX into haem is relatively slow, such cells tend to accumulate photosensitizing concentrations of Pp IX. Pp IX photosensitization can be induced in cells of the epidermis and its appendages, but not in the dermis. Moreover, since ALA in aqueous solution passes readily through abnormal keratin, but not through normal keratin, the topical application of ALA in aqueous solution to actinic keratoses or superficial basal cell or squamous cell carcinomas induces Pp IX photosensitization that is restricted primarily to the abnormal epithelium. Subsequent exposure to photoactivating light selectively destroys such lesions. In our ongoing clinical trial of ALA-induced Pp IX photodynamic therapy, the response rate for basal cell carcinomas following a single treatment has been 90% complete response and 7.5% partial response for the first 80 lesions treated. The cosmetic results have been excellent, and patient acceptance has been very good.

Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy.

Abstract: The tissue photosensitizer protoporphyrin IX (PpIX) is an immediate precursor of heme in the biosynthetic pathway for heme. In certain types of cells and tissues, the rate of synthesis of PpIX is determined by the rate of synthesis of 5-aminolevulinic acid (ALA), which in turn is regulated via a feedback control mechanism governed by the concentration of free heme. The presence of exogenous ALA bypasses the feedback control, and thus may induce the intracellular accumulation of photosensitizing concentrations of PpIX. However, this occurs only in certain types of cells and tissues. The resulting tissue-specific photosensitization provides a basis for using ALA-induced PpIX for photodynamic therapy. The topical application of ALA to certain malignant and non-malignant lesions of the skin can induce a clinically useful degree of lesion-specific photosensitization. Superficial basal cell carcinomas showed a complete response rate of approximately 79% following a single exposure to light. Recent preclinical studies in experimental animals and human volunteers indicate that ALA can induce a localized tissue-specific photosensitization if administered by intradermal injection. A generalized but still quite tissue-specific photosensitization may be induced if ALA is administered by either subcutaneous or intraperitoneal injection or by mouth. This opens the possibility of using ALA-induced PpIX to treat tumors that are too thick or that lie too deep to be accessible to either topical or locally injected ALA.

Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): mechanisms and clinical results

Abstract: 5-Aminolevulinic acid (ALA), when added to many tissues, results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway, to produce a photodynamic effect when exposed to activating light. Therefore, ALA is the only photodynamic therapy (PDT) agent in current clinical development that is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous superficial and nodular basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and in human clinical studies has shown selective formation of PpIX within the endometrium. PpIX induced by ALA application has also been used as a fluorescence detection marker for photodiagnosis (PD) of cancer and dysplastic conditions of the urinary bladder and other organs. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. The current state of knowledge of the mechanisms of endogenous topical and systemic photosensitization using ALA, the results of published clinical trials, and possible methods of increasing the efficacy of endogenous photosensitization for ALA PDT are reviewed in this paper.

Non-invasive technique for obtaining fluorescence excitation and emission spectra in vivo.

Abstract: An intensified photodiode array forms the heart of a sensitive spectrophotofluorometry system that permits the rapid and non-invasive determination of fluorescence emission spectra in the skin of living, non-anesthetized animals. Using this system, we found it possible to obtain good emission and excitation spectra of the material responsible for the weak red fluorescence that characterizes normal mouse skin, and to follow the biosynthesis and subsequent clearance of protoporphyrin IX in the skin of non-anesthetized mice that had been given various doses of the porphyrin precursor 5-aminolevulinic acid.

The possible role of ionic species in selective biodistribution of photochemotherapeutic agents toward neoplastic tissue.

Abstract: Photochemotherapeutic agents are photosensitizers that are selectively retained by neo-plastic tissue. When tumor tissue containing these drugs is irradiated with visible electromagnetic radiation, the photosensitizing reaction may lead to tumor eradication, termed photodynamic therapy. Exogenous photosensitizers commonly used in clinical trials are mainly porphyrin derivatives. Phthalocyanines are currently being investigated as “second generation” photochemotherapeutic agents. The mechanism by which these photosensitizers are selectively retained in neoplastic tissue is unclear. This review examines the role of tissue and cellular pH as a factor in selective biodistribution. The pH values of normal and tumor tissue are summarized and the ionic species distribution diagram of porphyrins is presented. A two-fold mechanism of selective biodistribution is advanced, one involving normal tissue vs. tumor tissue selectivity, the other involving intracellular vs. intercellular distribution of sensitizer ionic species.

Photodynamic therapy for cancer

Abstract: The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

Photodynamic Therapy

Abstract: Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrin) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed. Technical issues regarding light dosimetry are also considered.

Photodynamic therapy of cancer: An update†‡

Abstract: Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

How does photodynamic therapy work

Abstract: Those readers already familiar with the field of photodynamic therapy (PDT)t will consider this title somewhat presumptuous since it implies that the answer to the posed question is known. Indeed, answers to many questions regarding PDT have been found over the past decade, but a comprehensive understanding of all mechanisms involved in PDT tumor destruction has not yet emerged. This paper will attempt to deal with this complex subject by giving a sequential account of the effects occurring during PDT tissue treatment on a cellular and tissue level. Photodynamic therapy is based on the dye-sensitized photooxidation of biological matter in the target tissue (Foote, 1990). This requires the presence of a dye (sensitizer) in the tissue to be treated. Although such sensitizers can be naturally occurring constituents of cells and tissues, in the case of PDT they are introduced into the organism as the first step of treatment. In the second step, the tissuelocalized sensitizer is exposed to light of wavelength appropriate for absorption by the sensitizer. Through various photophysical pathways, also involving molecular oxygen, oxygenated products harmful to cell function arise and eventual tissue destruction results. In keeping with the chronological nature of this review, the subject matter will be divided into the