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The porphyrin handbook - Kadish K.M.

Kadish K.M. The porphyrin handbook - Academic press, 2000. - 368 p.
Download (direct link): kadishsmishgulilard2000.djvu
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has led to a large number of experimental and clinical studies on a
variety of tumor types.15-21 At the time of this writing, PDT with
Photofrin (a purified version of HpD) has been approved in Canada
(bladder and esophageal cancer), the Netherlands and France (esophageal,
early- and advanced-stage cancer), Japan (early-stage lung, esophageal,
gastric, cervical and cervical dysphasia), and in the United States for
advanced-stage esophageal cancer and early-stage lung cancer.22 23
Obviously, PDT has emerged as a promising cancer treatment modality.
B. MECHANISMS OF TUMOR NECROSIS
PDT is based on the accumulation of a photosensitizer in malignant tissue
after the administration of the photosensitizer. Subsequent illumination
with light of an appropriate wavelength creates a photochemical reaction,
a so-called photodynamic effect (photochemical reaction producing singlet
oxygen) that results in tissue destruction.2425 This process is described
in the modified Jablonski diagram (Figure 1).
Briefly, following the absorption of light, the sensitizer is
transformed from its ground singlet state (SQ) into an electronically
excited triplet state [(Tb(~ 10 2 s)] via a short-lived excited singlet
state 10~6s)]. The
excited triplet can undergo two kinds of reactions. First, it can
participate in an electron-transfer process with a biological substrate
to form radicals and radical ions which, after interaction with oxygen,
can produce oxygenated products such as superoxide ion, 02 (Type I
reaction).
Alternatively it can undergo a photochemical process known as a Type II
reaction25 which results in the conversion of stable triplet oxygen (302)
to the short-lived but highly reactive singlet oxygen (*02), the putative
cytotoxic agent. In water, the lifetime of 2 is approximately 1 -3 )j.s,
whereas in most organic solvents the lifetime is 4-50 times longer.
However, the lifetime of 2 is considerably shorter in cellular systems,
ranging from 100 ns in the lipid regions of membranes to 250 ns in the
cytoplasm.26 Therefore, the diffusion range of *02 is predicted to be
limited to approximately 45 nm in cellular media.27 Because the diameter
of human cells ranges from approximately 10 to 100 , they cannot
diffuse more than a single cell length.28 Thus, the site of the primary
generation of *02 determines which subcellular structures may be accessed
and attacked. Singlet oxygen is a powerful, fairly indiscriminate oxidant
that reacts with a variety of biological molecules and assemblies. It is
generally agreed that singlet oxygen is the key agent of cellular damage.
In other words, the Type II reaction predominates over the Type I,
although there is indication that superoxide ion (02 ) may also be
involved in some aspects of PDT damage.29
Mitochondria have been proposed as a major subcellular target of the
photodynamic effect, although other reported target organelles include
plasma membranes, lysosomes and nuclei.30 34 It was reported that
photodynamic treatment can also result, directly or indirectly, in damage
to DNA.35'36 However, there is evidence that such damage may not
necessarily be lethal to tumor cells.37
The major mechanism of tumor necrosis with Photofrin is believed to be
due to damage to the tumor vasculature that leads to blood stasis, thus
starving the tumor of oxygen and nutrients.38 In the initial phase after
irradiation, the plasma membranes and the membranes of mitochondria and
lysosomes start to disintegrate, followed by a continuous depletion of
the intracellular ATP pool which has drastic consequences for all energy-
consuming processes.39 It is also believed that the breakdown of cellular
membranes causes a rapid liberation of phospholipids, especially arachi-
donic acid, which leads to the release of an array of vasoactive and
inflammatory mediators (thromboxanes, prostaglandins and leukotrienes).40
Together, the generated substances initiate an acute inflammation and
edema, followed by vascular damage. The blood-flow stasis and
hemorrhaging finally create areas of local hypoxia and initiate necrotic
processes by nutrient deprivation. In response to the extraordinary
rapidity with which the platelets aggregate and adhere to damaged tissue,
the contents of their dense granules are discharged and various immune
mediators (IL-l/J, IL-2 and TNF-a) are released which augment the
pathological effects of the eicosanoids.41-46
It has been suggested that vascular shutdown is actually only one of
the several factors that contribute to PDT efficacy. Other mechanisms of
tumor necrosis proposed by various research groups include direct cell
killing47 48 and apoptosis.48-44
As discussed previously, the localization of HpD in tumors was known
since the early part of the twentieth century.4-5 However, the mechanism
for such tumor localization has not yet been found. Many factors such as
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