(The FASEB Journal. 2001;15:612-617.)
© 2001 FASEB
Reactive oxygen-dependent production of novel photochemotherapeutic agents
SHAZIB PERVAIZ1
Department of Physiology, National University of Singapore, Singapore 117597
1Correspondence: Department of Physiology, National University of Singapore, 2 Medical Dr., Singapore 117597. E-mail: phssp{at}nus.edu.sg
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ABSTRACT
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The reactive nature of species derived from oxygen, such as singlet
oxygen and hydrogen peroxide, has been exploited in the clinical
setting for targeting bacteria, viruses, and tumor cells by
photodynamic excitation of a variety of chromophores. This modality,
termed photodynamic therapy (PDT), is currently being used to treat
some forms of cancer. However, the applicability of conventional PDT is
limited due to the absolute dependence on simultaneous exposure of the
target to the photoactive compound and light. In 1990, we demonstrated
that the need for simultaneous exposure of the biological target to
light and photosensitizer could be circumvented by prior exposure
(activation) of the sensitizer molecule to light and its subsequent use
as any other anti-cancer or anti-viral drug. By dint of the nature of
the protocol, this process was termed preactivation. Since
then, the generation of biologically active molecules in
vitro by preactivation has been validated using a variety of
chromophores, such as merocyanine 540, Photofrin II, and naphthalimide.
Here we briefly review the role of reactive oxygen species in the
photodynamic effect, and provide an explanation for the mechanism of
preactivation. We propose that photo-oxidation not only
provides a novel means for the generation of biologically active
molecules, but could also explain, at least in part the mechanism of
conventional PDT. It is likely that the light-dependent breakdown of
the chromophore to generate novel active compounds, in addition to
reactive oxygen species, also contributes to the photodynamic damage
observed on simultaneous exposure of the chromophore and target tissue
to light during PDT.–Pervaiz, S. Reactive oxygen-dependent production
of novel photochemotherapeutic agents.
Key Words: PDT • photodynamic reaction • photosensitizer • mitochondrial permeability
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BACKGROUND
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ACCORDING TO THE postulates of the standard
evolutionary theory, the first living organisms evolved in the absence
of molecular oxygen. With the appearance of plants, this reducing
environment was transformed over a period of time and molecular oxygen
began to accumulate, reaching its present concentration of 
20%.
Just as the appearance of oxygen made aerobic respiration possible and
provided a shield against solar ultraviolet (UV) radiation by ozone
formation, the toxic potential of oxygen was also recognized, as oxygen
and some of its derivatives are highly reactive (1)
. Some
of these derivatives are produced by metabolic reactions (2
, 3)
; of special pertinence to this study, several are produced by
sensitized photobiological processes involving visible and UV
radiations (4
, 5)
.
The reactive nature of species derived from oxygen has been exploited
in the clinical setting for targeting bacteria, viruses, and tumor
cells by photodynamic excitation of a variety of chromophores. This
modality, termed photodynamic therapy (PDT), is currently being used to
treat some forms of cancer (6
7
8
9)
. However, the
applicability of conventional PDT is limited due to the absolute
dependence on simultaneous exposure of the target to the photoactive
compound and light. To circumvent this problem, a novel approach,
termed preactivation (10
, 11)
, was developed
that involved exposure of the chromophore to light prior to its use in
biological systems. The photo-exposed compound could then be used as an
anti-cancer or anti-viral agent without further dependence on light. It
is the purpose of this commentary to briefly review the role of
reactive oxygen species in the photodynamic effect and provide an
explanation for the mechanism of preactivation.
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THE PHOTODYNAMIC REACTION
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Although the use of natural products for their therapeutic
photodynamic activity goes back to human’s earliest research efforts,
the first experimental evidence of photosensitization was reported
around the turn of the century from von Tappeiner’s laboratory in
Munich. One of his medical students, Oscar Raab, observed that low
concentrations of acridines in the presence of light could be lethal to
the protozoan paramecium (12)
. Tappeiner and his
biomedical colleagues contended that these photobiological reactions
were highly dynamic and should be distinguished from photosensitization
of photographic plates by certain dyes (13)
. Hence, the
term photodynamic reaction was coined for all
photobiological reactions occurring in the presence of molecular oxygen
(14)
.
With the advent of the quantum theory and modern photochemistry, it
became obvious that limits on the photobiological processes were set by
the absorption spectrum of the light-absorbing substances or
photosensitizers. For a substance to be an efficient photosensitizer,
it must be capable of being excited, upon exposure to light, to a
relatively long-lived, energy-rich form termed the triplet
state (15
, 16)
. Organic photosensitizer molecules in
the dark almost always exist in the ground state; in this state, the
molecule has no unpaired electron spin. Upon absorption of a photon, an
electron in the sensitizer shifts to a higher orbital that could
undergo fast spin inversion to generate the triplet state,
containing two unpaired electrons (type I reaction) (4
, 17)
. The metastable triplet state of the photosensitizer could
then collide with certain biomolecules, such as molecular oxygen, with
the subsequent transfer of energy (type II reaction) (16
, 17)
and the return of the photosensitizer to the ground state to
carry on another interaction with a photon. The transfer of energy from
the triplet photosensitizer to molecular oxygen results in the
generation of the highly toxic activated oxygen molecule singlet oxygen
(1O2), which has a very short lifetime in
biological systems (<40 nanoseconds) and a short radius of action
(<0.02 µm) (18)
.
Apparently, the earliest attempts to exploit the phenomenon of
photosensitization for potential antitumor therapy were made by
Jesionek and Tappeiner in 1903 by light exposure of tumors in the
presence of eosin (19)
. The modern interest in PDT for
cancer therapy began with Lipson and Schwartz around 1960, who used a
fluorescent tumor localizing mixture of porphyrins, termed the
hematoporphyrin derivative (20
, 21)
. Since their
pioneering work, compounds including Photofrin, purpurins, xanthenes,
phthalocyanines, oxazines, cyanines, chlorins, and others have been
tested in vitro and in vivo with some success
(6
, 22
23
24
25
26)
. Membranous intracellular organelles such as
mitochondria, lysosomes, and nuclei, apart from the tumor vasculature,
are potential targets for attack by 1O2
generated on photoactivation of the sensitizer (27
, 28)
.
However, due to the limited migration of 1O2
from the site of formation (18)
, the initial damage is
closely related to the localization of the sensitizer. The potentially
lethal damage can take the form of 1O2-mediated
lipid peroxidation (29)
, and oxidative modification of
membrane proteins (30)
. Depending on the target organelle,
both necrotic and apoptotic forms of cell death have been reported in
cells and tissues after PDT (31
, 32)
. Photosensitizers
that predominantly bind to the plasma membrane may render a necrotic
phenotype, whereas mitochondrial specific sensitizers could lead to the
induction of mitochondrial permeability transition (MPT) and leakage of
proapoptotic factors into the cytosol (33)
, thereby
triggering the apoptotic caspase cascade (34)
. Thus, the
efficacy of PDT is dependent on the in situ generation of
1O2 upon photo-exposure of the sensitizer and
on the ready accessibility of susceptible lipids and proteins within
the bilayer.
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THE CONCEPT OF PREACTIVATION-OXIDATIVE DEGRADATION OF THE
PHOTOSENSITIZER
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Given the absolute requirement for the simultaneous exposure of
the target to the photosensitizer and light, the applicability of PDT
is limited to solid and accessible tumors, and for extra corporeal
purging of autologous bone marrow prior to transplantation (8
, 35)
. Early in 1988 our group became interested in looking for
ways to separate the process of photoactivation from the actual
biological activity. We hypothesized that the need for simultaneous
exposure of the biological target to light and photosensitizer could be
circumvented by prior exposure (activation) of the sensitizer molecule
to light and its subsequent use as any other anti-cancer or anti-viral
drug. By dint of the nature of the protocol, this process was termed
preactivation. The preactivated compound(s) could then be
tested for anti-tumor or anti-viral activity without further dependence
on light.
At the time we developed this concept, we were involved in studying the
photodynamic potential of the lipophilic polymethine dye merocyanine
540 (MC540) (36
, 37)
, a photosensitizer known for its
relatively high tumor selectivity (36
, 38
39
40
41)
. Studies
showed that MC540 was an excellent photodynamic agent against leukemia
and lymphoma cells with minimal nonspecific cytotoxicity (40
, 42
43
44)
. Hence, our initial studies to investigate
preactivation were carried out with MC540 exposed to 514 nm
(close to the absorption maximum) of laser light. Preactivated MC540
(pMC540) was then mixed in the dark with tumor cells or normal cells to
determine the anti-proliferative activity. The cytotoxicity of pMC540
was significantly higher (70-90%) against a variety of tumor cell
lines than normal peripheral blood mononuclear cells (<20%), and the
electron micrographs showed a progression toward apoptosis in majority
of the cells (10)
, with minimal toxicity to normal blood
cells in vitro and in vivo (10
, 45)
.
In addition, the life span of L1210 leukemia-bearing mice treated with
pMC540 was prolonged as compared to the control group administered the
native (nonactivated) MC540. pMC540 was also effective in almost
complete inactivation of cell-free herpes simplex and human
immunodeficiency viruses (11
, 46)
. In addition, the
anti-tumor activity of pMC540 was mediated by intracellular caspases
(47)
, thus highlighting the apoptotic potential of the
photoactivated mixture. Thus, contrary to the general belief that the
activity of the photosensitizer was dependent on the close proximity of
the biological target at the time of irradiation of the sensitizer, the
preactivated chromophore still retained anti-tumor activity
without further dependence on light.
Although the preactivated mixture of MC540 contained detectable levels
of reactive oxygen species, such as hydrogen peroxide
(48)
, the biological activity of pMC540 was retained for
up to 30 days when stored in the dark at -80°C, thus making the
requirement of 1O2 in the cytotoxic activity
superfluous; the half-life and diffusion range of
1O2 in aqueous media are extremely short
(18)
. However, the activity of pMC540 was significantly
reduced (50%) on light exposure in the absence of molecular oxygen,
thus suggesting that reactive oxygen, though not required for the
biological activity, was necessary during the process of
preactivation. Photochemical studies revealed that the
triplet formed by direct photo-excitation of MC540 was quenched by
molecular oxygen with the resultant formation of
1O2 (49
50
51)
; however, there was a
lack of correlation between 1O2 yields and the
photodynamic effectiveness of MC540 (52)
. Thus, in view of
the inherent photolability of some photosensitizers, cyanines in
particular, the likely scenario is a complete destruction of the dye by
1O2-mediated photo-oxidation (51
, 53)
. Consistent with this scenario, spectral analysis of the
preactivated MC540 mixture showed a complete shift of the absorption
maximum from 568 nm (MC540) to 280 nm (10)
, suggesting
complete photo-degradation (bleaching) of the parent sensitizer MC540,
which could be triggered by reaction with excited oxygen. Further
analysis of the pMC540 mixture by high-performance liquid
chromatography showed that the elution profile was completely different
from the parent molecule (MC540), strongly suggesting the breakdown of
the parent compound (10)
. These findings agree with
reports that 1O2 or other reactive oxygen
species produced on photoactivation could ‘back attack’ the
photosensitizer molecule itself (51)
, leading to rapid and
irreversible oxidation of the compound.
The photochemical transformation of MC540 was further investigated by
Franck and Schneider. They identified three novel photo-oxidation
products on irradiation of MC540 in methanol, namely,
merodantoin, merocil, and meroxazole
(53)
. Their study provided direct evidence that chemically
reactive 1O2 was sufficiently available to
trigger photo-oxidation of MC540. According to their model the central
polymethine chain of MC540 was attacked by
1O2, leading to the generation of
intermediates and subsequently to the new photoproducts. These results
provide further impetus to the hypothesis that
1O2 produced during conventional PDT or
preactivation could result in oxidative degradation of the
sensitizer molecule, and the resultant photoproducts may account for
the observed biological activity. A probable scenario is outlined in
Fig. 1
whereby direct exposure of a photosensitive chromophore to light
results in the generation of a triplet state of the chromophore. The
triplet formed by light excitation can be quenched by molecular oxygen
with the direct transfer of energy and the resultant formation of
reactive oxygen species (such as 1O2); this
energy transfer reaction results in the decay of the triplet state
chromophore back to the ground state. The activated oxygen thus formed
could attack the chromophore, resulting in the breakdown of the parent
compound to generate novel photoproducts. This hypothesis is in line
with the studies demonstrating light-induced bleaching or
photo-oxidation of MC540 and the subsequent generation of the
photoproducts (51
, 53)
.
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Figure 1. Photo-exposure of the sensitizer molecule leads to the generation of
photoexcited triplet sensitizer (sesitizer*). The excited sensitizer
then reacts with molecular oxygen to generate singlet oxygen
(3O2) or other reactive oxygen radicals (?),
which can back attack and photo-oxidize the sensitizer, resulting in
novel biologically active photo products.
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It is now well established that caspase activation, induction of MPT,
and release of cytochrome c are essential components of the
apoptotic pathway (34
, 54
, 55)
; hence, the realization
that drugs that directly activate caspases and/or target mitochondrial
structures could have potential for use as chemotherapeutic agents to
trigger effective apoptosis in tumor cells. Although the involvement of
the apoptotic pathway in conventional PDT-induced tumor cell lysis was
reported as early as 1991 by Agarwal et al. (56)
,
subsequent studies have demonstrated that mitochondrial events may be
critical in the execution of PDT-induced apoptosis (33
, 57)
. The photo-oxidized mixture of MC540 and two of its recently
purified photoproducts, C1 (identical to merodantoin) and C2 (identical
to merocil), induce caspase-dependent apoptosis in human tumor cell
lines (47
, 58)
. Both C1 and C2 as well as a third
intermediate product C5 trigger the cytosolic translocation of
cytochrome c from mitochondria by mechanism(s) dependent (C1
and C5) or independent (C2) of the MPT(59)
. It is
plausible that in addition to the local effect of conventional PDT
explained by the light-dependent production of reactive oxygen, the
generation of light-induced breakdown products could account for the
observed anti-tumor activity of the photosensitizer. Thus, at least in
the case of MC540, and perhaps other lipophilic agents with
predilection for mitochondrial membrane structures, light exposure of
cells loaded with the photosensitizer could result in direct toxicity
due to 1O2 production and in part to
1O2-dependent breakdown of the chromophore to
generate novel compounds with the ability to trigger molecular events
associated with apoptosis.
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THE ISSUE OF TARGET SPECIFICITY?
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You may wonder as to my use of the [mark of interrogation]
here. Indeed, the biggest challenge in effective anti-cancer drug
design and development is to achieve a high degree of anti-tumor effect
with minimal damage to the healthy tissues. The overall objective is to
identify relatively small molecules with predilection for molecular
target(s) truly specific for malignant cells. It is well established,
though poorly understood, that photosensitizers used in conventional
PDT exhibit a higher degree of selectivity for tumor tissues, though
not entirely innocuous to normal tissues (60)
. This has
been attributed to leaky vasculature of tumor cells, a high amount of
lipid favoring lipophilic sensitizers (61)
, a decreased pH
in tumor tissues (62)
, and a slower rate of clearance of
hydrophobic sensitizers due to reduced lymphatic drainage in tumor
tissues (63)
. The ultimate effect after light activation
is therefore closely related to the localization of the sensitizer
(28
, 64
, 65)
.
In light of this, it would be logical to assume that prior
photo-oxidation of the sensitizer could abrogate the enhanced tumor
localization observed with conventional PDT. At least in the case of
MC540, it is interesting that a photo-oxidized mixture of MC540 still
exhibited relatively higher cytotoxicity against tumor cells in both
in vitro and in vivo systems (10
, 45)
. The precise mechanism of this preferential activity is not
well understood, but it should be pointed out that the process of
photo-oxidation leads to the generation of novel small molecules that
may have the same therapeutic potential as any other natural or
synthetic anti-cancer agent. Indeed, the purification of three
photoproducts of MC540 and their ability to activate effector
components of the cell’s suicide program already suggest that this
novel modality could be exploited for the generation of potential
candidate compounds. First, once a biologically active agent is
identified, derivatives of the active compounds could be developed that
display more desirable pharmacological properties with minimal side
effects. This scheme of events was successfully used in the development
of first-, second-, and third-generation vinca alkaloids, antifolates,
and alkylating agents. Second, with the tremendous advancement in
technologies aimed at enhancing the pharmacodistribution properties of
anticancer drugs vis à vis drug delivery systems
(66)
, a significantly enhanced targeting of cytotoxic
drugs to tumor tissues could be accomplished (67
, 68)
.
Indeed, such delivery vehicles have already been successfully used in
conventional PDT for selective loading of photosensitizers in tumor
tissues (69
, 70)
. Liposome-associated photosensitizers
exhibit greater efficiency and tumor specificity, and hence some
second-generation photosensitizers are formulated in lipid-based
delivery systems (6)
. In addition, the increased
proliferation rate of tumor cells is known to selectively sensitize
tumor cells with a high growth fraction to chemotherapeutic agents.
Thus, the innovative use of a well-known concept of photoexcitation for
the generation of biologically active molecules and an investigation of
their potential for clinical use could definitely add to our repertoire
of weapons in the battle, not only against cancer but other
life-threatening diseases, such as HIV/AIDS.
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CONCLUDING REMARKS
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Our studies have successfully advanced the hypothesis that novel
biologically active compounds could be generated by photo-oxidative
degradation of a photosensitizer. Although, the bulk of our studies has
been performed with MC540 and its photoproducts, the concept is
applicable to sensitizers that yield appreciable amounts of
1O2 or other reactive intermediates upon light
exposure. In this respect, Photofrin II (6)
, which yields
significantly high amounts of 1O2 upon light
exposure, has been successfully preactivated
(71)
; however, the reactive intermediates have yet to be
identified. Similarly, another photosensitizer, naphthalimide, has been
reported to generate reactive photoproducts with anti-viral activity in
cells infected with HIV or HTLV-1 (72)
. More recently, our
preliminary data strongly support a similar mechanism for another
potential photodynamic agent, hypericin (St. John’s wort) (73
, 74)
. Whereas hypericin in the dark is minimally toxic to tumor
cells, upon photo-induced preactivation the anti-tumor activity is
significantly enhanced (S. Pervaiz et al. unpublished results). These
findings suggest a possible common mechanism applicable to some
chromophores, whereby exposure to light results in the generation of
biologically active intermediates upon breakdown of the parent compound
with potential for use as chemotherapeutic agents. Photo-oxidation does
not only provide a novel means for the generation of biologically
active molecules, but the identification of breakdown products could
also explain for the mechanism of conventional PDT. It is likely that
the light-dependent breakdown of the chromophore to generate novel
active compounds, in addition to reactive oxygen species, contributes
to the photodynamic damage observed on simultaneous exposure of the
chromophore and target tissue to light during PDT.
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ACKNOWLEDGMENTS
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I would like to acknowledge the contributions of so many whose work
could have been inadvertently left out and to thank Dr. Kirpal S.
Gulliya for his contributions to the concept and with whom I shared
many years of excellent working relationship. I also deeply appreciate
Professor Barry Halliwell and Dr. Marie-Veronique Clément for
useful comments and discussions.
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ABSTRACT
BACKGROUND
