Laryngology Seminar
Photodynamic Therapy (PDT)
R3 蘇旺裕 2002/04/24
Introduction
 Photosensitizer: compounds that are capable of absorbing light of a specific wavelength and
transforming it into useful energy
 cold photochemical reaction
photosensitizer+ O2→wait a period to allow target tissue distribution→+ light (200~1000s)
 Preferentially accumulate in diseased tissue (possible due to leaky vasculature, high cell
proliferation rate, lower pH value, inefficient lymphatic drainage; etc)
 generate cytotoxic agents to induce the desired biological effect
 Light dose (J/cm2)= Dose rate (W/cm2) x Exposure time (sec)
Mechanism of Action
 Type I: hydrogen-atom abstraction
(more important at low O2 concentration)
 Type II: energy transfer (predominate)
Signal pathways after PDT
 1)Initiate a rescue response (stress protein); 2)undergoing cell death (Apoptosis or necrosis)4
 Levels: Mitochondria, lysosome, plasma membranes (varies greatly, much unknown)
Nuclei: seemed no accumulation
 Tumor necrosis via vascular shutdown
Advantages
 less morbidity, better functional & cosmetic outcome
 normal healing & re-epithelialization
neglectable effects on underlying functional structures
no tissue heating (connective tissue such as collagen & elastin- largely unaffected)
 No accumulative toxicity, can be use repeatedly (metabolized rapidly)
not teratogenic (seemed no effect on nuclei)
 local or no anesthesia, short time, simple procedure
No admission with oral analgesic only
Photofrin® QLT PhotoTherapeutics (Vancouver, Canada), 1st generation
 haematoporphyrin derivatives
 haematoporphyrin+ 5% sulphuric acid (in acetic acid, at room temp)→+ aqueous base
(neutralized)→ a complex of mixture of dimmers & oligomers (ester and ester linkage)
 purified oligomer by HPLC/ size exclusion gel chromatography→90~95% active component
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readily taken up & retained by cutaneous tissue for up to 6~10 wk
IV, wait 48hr, absorption peaks between 400~650 nm (Max= 630nm)
tissue penetration= 0.7-1.0cm (increases with increasing wavelength)
marked skin photosensitivity (avoid bright sunlight)
Indication (superficial, early-stage cancer, or in hollow organs where light can be delivered)
 PROVED: early- & late-stage lung cancer, superficial & advanced esophageal cancer,
bladder cancer, superficial and early-stage gastric cancer, early stage cervical cancer, cervical
dysplasia
 Possible: Kaposi’s sarcoma, cancers of the head & neck, brain, intestine, lung, breast, skin,
urinary bladder, abdominal and thoracic cancer, psoriasis, arterial restenosis…
 Laryngeal cancer (Tis, T1, failed R/T)1,5
Intra-op adjuvant PDT for recurrent H&N ca13
papillomatosis, CIS, recurrent leukoplakia2
Not indicated
 T2, T3- CR but recurred locally (unable to deliver light to the entire tumor bed uniformly)
 Palliation- risky (organ perforation, vessel damage…)
Head & Neck Cancer- current results
 Photofrin (phase III), Photoeme (laryngeal cancer), Purlytin (preclinical), Foscan (phase III),
Phthalocyanine (phase I/II)
 Photofrin 2mg/kg, IV over 5 min5
48h after injection, Argon laser (630nm), deliver with a 400m fused silica optical fiber
light dose 80J/cm2, dose rate= 150 mW/cm2
 Observe signs of airway obstruction for 24hr
Decadron iv 1 dose + oral analgesics
 Max necrosis at 7 days post-Tx, complete healing by 4wk
Heal by epithelization instead of scarring (6-12mo)
Not due to thermal effect (need 41-43℃)12,14, temp rise of only 0.5~2.1℃
Ideal characteristics of photosensitizer
 chemically pure & of known and constant composition
 preferentially retained by the target tissue
 high photochemical reactivity (high triplet-state yields, long triplet-state lifetime, able to
effectively produce singlet oxygen & other reactive oxygen species)
 strong absorbance with a high extinction coefficient at a longer wavelength
 minimal dark toxicity, only be cytotoxic in the presence of light
 rapidly excreted from the body (low systemic toxicity)
 can use cheaper diode lasers
References
1.
Merrill A. Biel. Photodynamic Therapy and the Treatment of Head and Neck Neoplasia. Laryngoscope 108: 1259-1268, 1998.
2.
Merrill A. Biel. Photodynamic Therapy and the Treatment of Neoplastic Diseases of the Larynx. Laryngoscope 104: 399-405, 1994.
3.
Jens Feyh. Photodynamic treatment for cancers of the head and neck. J Photochem Photobiol B: Biol. 36(1996): 175-177.
4.
Anne C.E. Moor:Signaling pathways in cell death and survival after photodynamic therapy. J Photochem Photobiol B:Biol. 57(2000):1-13.
5.
Merrill A. Biel. Photodynamic Therapy and the Treatment of Head and Neck Cancers. J Clin Laser Med Surg. 14(5): 239-244, 1996.
6.
W. Beyer. Systems for light application and dosimetry in photodynamic therapy. J Photochem Photobiol B: Biol. 36(1996): 153-156.
7.
Biulio Jori. Tumour photosensitizers: approaches to enhance the selectivity and efficiency of photodynamic therapy. J Photochem
Photobiol B: Biol. 36(1996): 87-93.
8.
Leonard I. Grossweiner: PDT light dosimetry revisited. J Photochem Photobiol B: Biol. 38(1997): 258-268.
9.
R. Ebermann, G. Alth, M. Kreitner, A. Kubin. Natural products derived from plants as potential drugs for the photodynamic destruction of
tumor cells. J Photochem Photobiol B: Biol. 36(1996): 95-97.
10. Wesley M. Sharman, Cynthia M. Allen and Johan E. van Lier. Photodynamic therapeutics: basic principles and clinical applications. DDT.
4(11): 507-517, 1999.
11. Allan L. Abramson, Larry S. Hirschifield, Mark J. Shikowitz, Nestor X. Barrezueta. The Pathologic Effects of Photodynamic Therapy on
the Larynx- Experimental Study. Arch Otolaryngol Head Neck Surg. 114: 33-40, 1988.
12. Merill A. Biel. Photodynamic Therapy as an Adjuvant Intraoperative Treatment of Recurrent Head and Neck Carcinomas. Arch
Otolaryngol Head Neck Surg. 122: 1261-1265, 1996.
13. Allan L. Abramson, Nestor X. Barrezueta, Mark J. Shikowitz. Thermal Effects of Photodynamic Therapy on the Larynx. Arch Otolaryngol
Head Neck Surg. 113: 854-858, 1987.