Aust. N . Z . J . Surg. 19!

31,61,340-348 340

A HISTORY OF PHOTODYNAMIC THERAPY

AND J. s. HILL
M.D.DANIELL
Higginbotham Neuroscience Research Institute, Department of Surgery, Royal Melbourne Hospital,
Parkville, Victoria

The origins of light as a therapy in medicine and surgery are traced from antiquity to the modem day.
Phototherapy began in ancient Greece, Egypt and India but disappeared for many centuries, only being
rediscovered by Western civilization at the beginning of the twentieth century through the Dane, Niels Finsen,
and the Germans Oscar Raab and Herman von Tappeiner. The discovery of the tumour-localizing ability of
haematoporphyrin,together with its phototoxic effect on tumour cells led to the development of photodynamic
therapy, a promising tool in modem cancer treatment.

Key words: cancer, haematoporphyrin, history, laser, photodynamic therapy, phototherapy, tuber-
culosis, tumour.

Introduction photosynthetic process which forms the basis for

iife on this planet. Yet there are simultaneous
The use of light as a therapeutic tool in surgery is phototoxic reactions, the result of singlet oxygen
becoming increasingly important, with the routine
formation, that would prove rapidly lethal if they
use of lasers for photocoagulation and in the
were not quenched by the orange and yellow
photodynamic therapy of cancer. The use of light as
carotene pigments of plants. In humans, naturally
a therapy in human diseases has a very long history,
occurring porphyrins, usually in iron complexes
stretching back into antiquity. There was a long
such as haemoglobin, myoglobin and cytochrome,
period in which its uses were not appreciated, how-
are also essential for life and are operative in all
ever, and only this century, through photodynamic
aerobic cells. However, disturbance of synthesis of
therapy and psoralen molecules and ultraviolet A
porphyrins responsible for the haem group leads to
radiation (PUVA) therapy of some dermatological
a class of diseases called porphyrias, each with a
conditions, has light undergone a renaissance as a
unique pattern of over-production, accumulation
useful therapeutic tool in medicine and surgery.
and excretion of intermediaries of haem biosyn-
The rediscovery and development of phototherapy
thesis. The main clinical manifestations are inter-
is also remarkable in that it was not until the second
mittent episodes of nervous system dysfunction and
half of the 20th century that the English-speaking
sensitivity of the skin to sunlight. This skin photo-
world began to appreciate its full potential. It is
sensitization is due to porphyrin accumulation and
only by translating the old German, French and
Danish texts that the discoveries of these early the consequent photodynamic action, after light acti-
pioneers can be appreciated. The origins of photo-
vation, of singlet oxygen induced tissue damage. '**
Similar phototoxic reactions have been used for
dynamic therapy have been investigated by review-
the treatment of a variety of diseases including
ing this early literature that, until now, has been
psoriasis, vitiligo and, more recently, cancer, via
largely neglected. This paper traces the develop-
photodynamic therapy. This technique exploits
ment of light as a treatment and the use of pho-
naturally occurring but usually suppressed reac-
todynamic therapy in surgery. tions. A photosensitizing dye is administered which
The interaction of light with some living cells is localizes specifically in the tumour and is subse-
vital for their survival and yet under certain circum-
quently activated by light (usually a laser). When
stances can lead to their destruction. Light is neces-
the sensitizer absorbs light of the appropriate wave-
sary for the production of carbn dioxide and oxygen
in plants via its interaction with magnesium dihy- length it is converted from a stable electronic struc-
ture (ground state) to an excited state (singlet state).
droporphyrin, better known as chlorophyll, in the
The short-lived singlet state may undergo conver-
sion to a long-lived excited state (triplet state),
Correspondence: Dr M. D. Daniell. Department of Surgery, which is the photo-active species responsible for
Royal Melbourne Hospital, Parkville. Vic. 3052, Australia. the photochemical generation of cytotoxic prod-
Accepted for publication 12 December 1990. ucts. Interaction of the triplet state with oxygen
 PHOTODYNAMIC THERAPY
produces singlet oxygen, an electronically excited
state of oxygen which is highly reactive in biologi-
cal systems and leads to photo-oxidation and cell
death.’ The photosensitizer dyes used are usually
porphyrins, flat molecular tablets approximately
7A square with a central hole that can accommo-
date a metal ion.
History of phototherapy
The first uses of light as a therapeutic agent go back
many centuries. It was used by the Egyptians, Chi-
nese and Indians in the treatment of many diseases
including vitiligo, rickets, psoriasis, skin cancer
and even One of the earliest known
reports of the sun as a therapeutic agent was
heliotherapy, introduced by the Greeks 3000 years
ago. The Greeks preferred a form of heliotherapy
whereby total body exposure to the sun, or arena-
tion, took place as the participants lay nude in spe-
cially set aside areas. Herodotus, the renowned
physician of the 2nd century BC was the father of
heliotherapy . His teaching stressed the usefulness
of exposure to the sun for the restoration of health.
Sun worship was the basis of many ancient re-
ligions in Europe, Asia and the Americas and this
may have had as much to do with the healing prop
erties of the sun as with their importance to agricul-
ture. With the advent of Christianity both sun
worship and the use of sunlight as a healing
modality came to be regarded as pagan practices,
although they continued in many forms.
It was not until the late 18th century that the
beneficial effects of exposure to the sun became re-
established as effective therapy for rickets. A 19th
century physician, Cauvin, stated in 1815 that
‘Sunlight is a curative agent for scrofula, rickets,
scurvy, rheumatism, paralysis, swellings and
dropsy and muscle weakness’.6 Phototherapy was
developed into a science and popularized by the
Danish physician Niels Finsen who initiated the use
of carbon arc phototherapy for lupus vulgaris and
won the Nobel prize in 1903 for his w o k 7 Finsen
was born in the Faroe Islands and his interest in the
contrasts of light and dark in the Arctic Circle led
him to study the effects of light on living organ-
isms. Finsen conducted experiments on light and
published a paper in 1893on treatment of smallpox
with red light, which prevented suppuration of pus-
t u l e ~Later
. ~ he found actinic rays to be responsible
for the bactericidal property of sunlight, and this
enabled him to develop a method of treatment of
lupus vulgaris by ultraviolet rays. The Finsen Light
Institute was founded in Copenhagen in April 18%
and is still an active establishment. Princess Alex-
andra, wife of the future Edward VII, was respon-
sible for introduction of her countryman’s discovery
to England. By the turn of the century she was
341
encouraging doctors to apply phototherapy at the
London Hospital, of which she was president. A
plaque at the base of a statue of Queen Alexandra
commemorates her contribution (Figs 1, 2). Today
phototherapy is most widely used in the treatment
of infants with neonatal jaundice, a treatment
developed by Cremer er al. at Rochford Hospital
in &sex more than 30 years ago (Figs 3-5).7’
Ng. 1. Plaque commemorating Queen Alexandra visiting
patients with lupus vulgaris beiig treated with photo-
therapy. Located on pedestalof statue of Queen Alexandra,
London Hospital, London. From New Scientist, 28
January 1989.
History of photochemotherapy
Photochemotherapy, or use of an exogenous sen-
sitizer to absorb photons and then react for a
therapeutic effect, also has a long history.
Psoralens were used in India as early as 1400BC.’
Detailed descriptions in India’s s a d book
Atharva-Veda (1400BC) indicate that Hindus prac-
tised the ancient Ayurvedic system of medicine using
psoralens obtained from the seeds of Psoralea cory-
lifoliu for repigmentation of vitiligenous skin.
Around the 12th century AD, the Egyptians ob-
tained psoralens from another plant, Anmi majus,
which grows along the south bank of the Nile river,
and used them in the treatment of leucoderma. It
was many hundreds of years before Kalbrunner iso-
lated the chemical bergapten or 5-methoxypsoralen
from bergamot oil in 1834, but even he did not
think to apply his lotion in the same way as the
earlier civilizations. It was not until 1974 that
PUVA was found to be effective in the treatment of
psoriasis.’ PUVA involves use of psoralen dyes
activated by ultraviolet A radiation - that is. light
between 320 and 400nm.Subsequently, the devel-
opment of an artificial, high intensity source of
UV-A radiation made PUVA practical for the treat-
ment of psoriasis and vitili o and, more recently, as
a part of immunotherapy.B
It was at the beginning of the 20th century that
Oscar Raab, a medical student of Professor Herman
342
Fig. 2. Photodynamic therapy today. Gold vapour laser in operation at the Royal Melbourne Hospital.
Fig. 3. 'Le Chalet', the first Dr Rollier's Clinic (opened
in 1903) for treatment of patients suffering from surgical
tuberculosis.
Fig. 4. The school in the sun for delicate and predisposed
children. 'Les Noisetiers' at Cergnat near Leysin.
DANIELL AND HILL
von Tappeiner in Munich, first examined photosen-
sitized reactions in a scientific way and introduced
the subject to Western medicine. loVon Tappeiner's
initial interest was in identifying the process by
which quinine was effective in malaria whereas
other chemicals, in particular acridine, were more
toxic against the protozoan in vitro but were not
effective in vivo. Hence, von Tappeiner investigated
the properties of acridine (a coal tar derivative),
initially demonstrating its potency in vitro with
serial dilutions. However, Oscar Raab, who was
performing the experiment, came upon an apparent
paradox at the lowest limit of concentration. Ini-
tially the paramecia all died 60- min
after acridine at dilutions of 1-2OOOO had been
added. In a subsequent experiment they lived for
800-1OOOmin, a markedly different result. The
only difference in protocol between the two experi-
ments was a great thunderstorm which occurred
during one, causing distinctly different light condi-
tions, and so they began to wonder if it was the
light that had caused the difference in their results.
Subsequent experiments confirmed that acridine
and light increased the toxicity whereas acridine
alone, light alone, or acridine exposed to light and
then added to paramecium were not toxic. Raab's
experiments identified the optical property of
fluorescence as that responsible for the in vifrotox-
icity and realized that it was not the light itself but
some product of the fluorescence that was active.
 PHOTODYNAMIC THERAPY
Fig. 5. Extensive lupus vulgaris. cured after I year of heliotherapy. Photographs from a collection of glass lantern slides
held in the Medical History Unit of the University of Melbourne.
Raab’s explanation for the toxic property of
fluorescence was incomplete, partly because of the
limited understanding of the physical nature of
fluorescence at that time. His hypothesis was of a
transfer of energy from light to chemical, as is seen
in plants following absorption of light by chloro-
phyll. This paper concluded with a prophecy of the
future application of fluorescent material as a
therapeutic agent in dermatology. ’’
Von Tappeiner took over Raab’s research and,
with a dermatologist named Jesionek, published
clinical data using eosin as a photosensitizer in the
treatment of skin cancer, lupus of the skin and
chondylomata of female genitalia.” In 1904 von
Tappeiner and Jodlbauer reported that the presence
of ox gen was a requirement for photosensitiza-
tion. Y In 1907 these experimentswere collated into
a book in which von Tappeiner coined the term
‘photodynamic therapy’ to describe the phenom-
enon of oxygen-dependent photosensitization. l4
The term ‘photodynamic therapy’ was used to
distinguish these reactions from the phenomenon of
photosensitization of photographic plates, which
was popular at the time and which was the basis for
modem photography. Von Tappeiner is probably
the most important early pioneer of photodynamic
therapy, clearly predicting the photochemothera-
peutic application of photosensitizers as early as
1900. He was also the first to attempt phototherapy
343
of tumours. Three patients with skin tumours had a
5% solution of eosin typically applied, in some
cases supplemented by intra-tumour injection dye.
The tumour area was irradiated with light, either
sunlight or an arc lamp, for several weeks, with
reported improvement. In 1905. the same investi-
gators reported on a further six patients.I5 In most
of these patients eosin was used at various concen-
trations, although the sensitizer was supplemented
with fluorescein in one case and sodium dichloro-
anthracine disulphonate in another, and one patient
was treated with Grubler’s magdalene red. Again,
favourable results were reported in most cases. The
first recorded instance of a photosensitizing drug
administered parenterally to humans was that of
eosin in 1900. Prime, a French neurologist, began
to administer eosin orally for the treatment of
epilepsy. He observed that dermatitis occurred on
areas of the body exposed to light.16
History of haematoporphyrin
The history of porphyrins and their role in medicine
is. by contrpt. very brief. Haematoporphyrin was
first made by Scherer in I 8 4 I . ” Scherer added con-
centrated sulfuric acid to dried blood and washed
the precipitate free of iron. When the iron-free resi-
due was treated with alcohol it took on a blood red
colour, and he was able to show in this way that
344
iron was not essential for the red colour of blood.
Three years later Mulder named this purple-red
substance iron-free haematin.” The spectrum of
this substance and its remarkable fluorescence were
described by Thudichum in 1867 in his re rt to the
Medical Officer of the Privy CounciLrHoppe-
Seyler (1871) was the first to describe the purple
substance found in iron-free haematin as haemato-
porphyrin.” The name porphyrin comes from the
Greek ‘porphuros’ meaning reddish purple. Prior to
this it was known as ‘cruentin’, being a product
extracted by alcohol and sulfuric acid from
haemoglobin. which was also known as cruorin.
The first studies of the biological properties of
haemato rphyrin were by Hausmann (1908) in
Vienna.‘He reported destruction of paramecia and
red blood cells, and observed in detail symptoms
and signs of sensitized mice on exposure to light.
Hausmann (191 I ) and Pfeiffer (191 I ) reported sen-
sitization in guinea-pigs and white mice with haem-
atoporphyrin, describing fairly acute, subacute and
chronic photosensitivity chan es and some photo-
toxicity with intense ? First proof that por-
phyrins could act as photosensitizing agents in
humans came when the German Friedrich Meyer-
Betz (1913) injected himself with 200 mg haemato-
porphyrin. Within minutes after light exposure he
noticed severe pain and swelling confined to the
light-exposed areasz4 He remained exquisitely
photosensitive for more than 2 months. This reac-
tion was studied more recently by Zalar et a / .
( 1973) in two patients similarly photosensitized
with haemat~porphyrin.~’ Meyer-Betz and the Ger-
man chemist Fischer made several observations on
the effect of porphyrin structure on photodynamic
activity. In 1912 they found that haematoporphyrin
sensitized mice but that mesoporphyrin did not, and
Fischer (1925) found uroporphyrin almost as photo-
toxic as haematoporphyrin.26 Hans Fischer was
inspired by and commenced a study of one of Gun-
ther’s original patients, a man named Petry, who
had been diagnosed as suffering from congenital
haematoporphyria. Between 1915 and 1945 he
made monumental contributions to porphyrin
chemistry, showing that the naturally occurring
porphyrins of excreta - uroporphyrin and copro-
porphyrin - were of a different structure than
haematoporphyrin. He was also the first to suggest
abandoning the prefix ‘haemato’. except where
specifically required. With the exception of Fis-
cher’s laboratory, most work in porphyrins was
halted by the First World War. A student of Fis-
cher. Max Lemberg, emigrated to Australia as a
refugee in the late 30s. He later wrote the first book
in English on p o r p h ~ r i n s . ~ ~
In the period between the wars there were two
significant advances in photodynamic therapy.
First, selective localization of porphyrins to
DANIELL AND HILL
tumours was observed by the Frenchman Policard
(1924) in Lyon, who noted the spontaneous fluores-
cence in experimental tumours exposed to a Woods
lamp and correctly attributed this finding to accu-
mulation of porphyrin in the turnour.” The second
major finding was by Auler and Banzer in Berlin,
who were the first to observe photodynamic action
involving haematoporphyrin on t u m o ~ r s In. ~ 1942
~
they investigated the uptake of haematoporphyrin
into tumour, proving conclusively its specific up-
take and retention, with higher levels in the tumour
than in the normal surrounding tissues. During their
investigations they noted that the fluorescing
tumours tended to be on the whole more necrotic
and so for the first time observed photodynamic
action by haematoporphyrin on tumours. They fol-
lowed up these findings with a series of experi-
ments using animals bearing Jensen’s sarcoma and
Flicks-Jobling carcinomas. They injected them
with photodyn (haematoporphyrin) and subse-
quently illuminated the tumours with a strong
quartz lamp. Sections of the tumours showed
marked necrosis and cystic softening. One animal
was left with only a superficial scab after 4 irradia-
tions -the tumour had been completely necrosed.
Experiments began on humans with tumours but
research was interrupted by the Second World
War.29 It was more than 20 years before their
experiments were repeated.
Post-war advances
The findings of Auler and Banzer did, however,
stimulate much work on accumulation and retention
of porphyrins. Figge (1948) showed selective reten-
tion in vivo and recognized the importance of
x
haematoporph rin as a potential tool for the diagno-
sis of cancer: Rasmussen-Tiurdal. Ward and Figge
(1955) studied haematoporphyrin and confirmed its
tumour-localizing ability in a variety of tumours.”
However, consistent uptake without large doses was
not possible and the associated risks of phototoxicity
made haematoporphyrin unsuitable as a diagnostic
aid in humans. Schwartz ct a/. (1955) investigated
the nature of haematoporphyrin and found it to be a
crude, variable mixture of numerous porphyrins,
many of which had different properties. With par-
tial purification, the pure haematoporphyrin was the
poorest localizer and it was the usually discarded resi-
due that showed the greatest affinity for turnours.32
Schwartz focused his attention on tests of the non-
haematoporphyrin fraction and made new prepara-
tions trying to purify this more active component.
Among these new porphyrin preparations was a
acetic-sulfuric acid porphyrin, which has come to
be known as haematoporphyrin derivative (HpD).
The discovery of HpD was another example of
serendipidity in science. In the process of produc-
 PHOTODYNAMIC THERAPY
ing non-haematoporphyrin fractions, Schwartz
used a basic purification system that included ex-
traction into a mixture of ethyl acetate and glacial
acetic acid, with subsequent esterification in sul-
furic acid. Much to his surprise, the product
showed enhanced localization in tumours, despite
producing a new compound. Further experiments
showed that it was the combination of glacial acetic
acid and sulfuric acid, with dissolution in dilute
alkali, that led to its improved properties. Although
Schwartz had failed to purify the porphyrin frac-
tions, he had produced a far more effective tissue
localizing agent (pers. comm.).
At this stage, Lipson from the Mayo Clinic was
convinced by Schwartz to drop his work on
haematoporphyrin and take over investigation of
this new derivative (Schwartz, pers. comm.). L i p
son, together with Baldes, showed enhanced local-
ization in malignant tissue, with improved
photodynamic properties. HpD also had a far more
constant composition than haematoporphyrin, al-
though it was far from being a pure substance.33*"
This material was used in humans to localize
tumours of the bronchus, oesophagus and cervix,
with good correlation between fluorescing sites and
biopsy-proven
Despite the preliminary studies of Auler and
Banzer and widespread investigation of the localiz-
ing properties of HpD, the use of photodynamic
therapy with HpD in humans did not begin until the
1960s. In 1966, Lipson er al. reported the first use
of HpD to treat cancer in a patient with a large,
ulcerating, recurrent breast carcinoma.38 The pa-
tient was treated with multiple HpD injections and
local exposure of the tumour to filtered light from a
xenon arc lamp. The lesion recurred after several
weeks but objective evidence of response was found.
Berg and Jungstaad in 1966 and 1967 examined
methylene blue, thiopyrinine and anachroquinine-
2-sulfonate as sensitizers with moderate success,
observing significant tumour destruction followed
by healing of superficial turn our^.^^*^
Effective destruction of tumour cells in vivo was
first shown by Diamond et al. (1972) using haema-
toporphyrin-sensitized glioma cells implanted sub-
cutaneously in rats and followed by fluorescent
lamp expo~ure.~' About the same time Dougherty
reported that fluorescein could act in a similar
way.42 Two years later, using an argon laser and
acridine dye, Thomson et al. effectively treated
mouse epithelial t ~ r n o u r s . Dougherty
~~ et al.
(1975) were the first to show long-term cures in
haematoporphyrin-sensitizedmice and rats bearing
a variety of tumours and irradiated with a xenon arc
lamp filtered to produce a wavelength greater than
600nm.'"' This was non-toxic to the animals and
there was minimal damage to overlying skin. In
1976, Kelly and Snell reported HpD uptake in
345
malignant and pre-malignant lesions of the bladder
and reported the treatment of a single case of blad-
der carcinoma using HpD and light from a mercury
lamp dirscted into the bladder by a glass light
guide.45 Following the promise of the in vivo test-
ing and encouragement from anecdotal reports. the
first systematic human trials were performed by
Dougherty er al. in 1978 on a series of 25 patients,
with complete or partial response in 111 of 113
cutaneous or subcutaneous malignant lesions.46
Tumours treated included carcinomas of the breast,
colon, prostate, squamous cell, basal cell and
endometrium, malignant melanoma, mycosis fun-
goides, chondrosarcoma and angiosarcomas. HpD
was injected intravenously at doses of 2.5 and
5 mgkg and a 5000mW xenon arc lamp with a
filter producing 600-700nm light was used 1-7
days after injection. No tumour was found to be
unresponsive.46 Since then, numerous studies have
reported the use of HpD-mediated photodynamic
therapy of a wide variety of tumours, notably blad-
der, lung, oesophagus, stomach (unpubl. data),
skin, gynaecological, head and neck, choroidal
melanoma and gli~ma.~'-~? The fmt photodynamic
therapy of human glioma using haematoporphyrin
derivative and helium neon laser was performed
by Pema (1980) and showed no improvement in
patient survival but some tumour necrosis.68 Since
then, trials run by Laws (1981), Wharen ef af.
(1983), McCullough et 01. (1984), Muller and Wil-
son (1990) and Kaye et al. (1988) have shown
significant success using photodynamic therapy,
especially at higher light doses, following introduc-
tion of the gold vapour l a ~ e r . ~ - ~ O
Present status of pbotoaylrpmic therapy and
luture directions
Today, more than 2000 patients have been treated
by photodynamic therapy in uncontrolled clinical
trials. Treatment of endobronchial cancer, superti-
cia1 bladder cancer, head and neck cancer, gynae-
cological cancer, gastrointestinal cancer, ocular
cancer, skin cancer and intracranial cancer using
haematoporphyrin derivative or its more purified
form, Photofrin 11, has shown encouraging results,
with tumour response rates of 50- 100%. Phase II1
clinical trials are currently being undertaken in
North America for lung cancer, superficial bladder
cancer and oesophageal cancer. Photodynamic
therapy is a technique that offers special advantages
as an adjuvant therapy of malignant brain tumours
as it has been shown to be an effective method of
controlling local tumour.
The major role of photodynamic therapy will
continue to be in more aggressive local control of
malignancy without extensive damage to surround-
ing normal structures. The major reasons for failure
346
of therapy are inadequate dosimetry of light and/or
sensitizer to the tumour; with these factors in mind,
a logical progression of research can be predicted.
Improvements in light dosimetry, including more 4.
efficient delivery to the site of action, better under-
standing of the optical properties of tissues, espe-
cially penetration depth, study of photosensitizer
quenching and photobleaching, and the develop-
ment of direct measurement of light fluorescence 5.
distribution during photodynamic therapy will im-
prove clinical results markedly. Many of these 6.
areas pose problems in basic physics and engineer-
ing which must be solved to realize the full poten- 7.
8.
tial of photodynamic therapy.
The other major area of research will involve the
development of more effective and more specific 9.
sensitizers. Haematoporphyrin derivative is a
mixture of porphyrins, many of which have been 10.
shown to be inactive in vivo. Development of pure
sensitizers will allow higher doses of more specific 1I .
sensitizer to be given without fear of unwanted skin
photosensitivity, the major side-effect of photo-
12.
dynamic therapy. It will also dramatically improve
our understanding of the mechanism of action,
especially with new advances in confocal micro- 13.
scopy. Also, sensitizers are being developed that
are activated at wavelengths greater than 630 nm,
allowing greater penetration of normal tissues.
With better understanding of the photophysics, 14. VON TAPFWNER
photochemistry and photobiology of photodynamic
therapy we should see marked improvement in the
clinical efficacy of this treatment modality. which 15.
had its beginning in prehistory, and be able to iden-
tify a clear indication for its use in the adjuvant
therapy of cancer. 16.
Acknowledgements 17.
18.
The authors thank Mr A. Kaye and Prof. G.J. A. 19.
Clunie for encouragement and advice in the prepa-
ration of this paper, Prof. H. Attwood of the Medical
History Unit at Melbourne University for the glass 20.
lantern slides and New Scientist magazine for the
photograph of the plaque. M.D.D. thanks V. Bet- 21.
tinger, who translated the original German texts.
We also acknowledge the assistance of Drs S. K. 22.
Schwartz and T. J. Dougherty in providing access
to unpublished material.
23. PFEIFFER
References
MEYERU. A. (1987) Porphyrias. In: Harrison's Prin-
ciples of Internal Medicine, I Ith edn (Eds E. Braun-
wald, K. J. Isselbacher, R. G. Petersdorf er 01.). 24. MEYER-BETZ
pp. 1638-43.
DEAN G. (1972) The Porphyrias, 2nd edn, Pitman
Medical Publishing Co., London.
BONNETT R. & BF~RENBAUM M. C. (1989) Porphyrins 25. ZALAR
as photosensitizers. In: Phorosensirising Compounds:
DANIELL AND HILL
Their Chemistry, Biology and Clinical Use (Eds G .
Bock & S. Hamett), pp. 40-53. John Wiley & Sons,
Chichester.
SPIKES J. D. (1985) The historical development of
ideas on applications of photosensitised reactions in
health sciences. In: Primary Photoprocesses in Eiol-
ogy and Medicine (Eds R. V. Bergasson, G. Jori,
E. J. Land & T. G. TNSCO~~). pp. 209-27. Plenum
Press, New York.
EPSTEIN J. M. (1990) Phototherapy and photochemo-
therapy. N . Engl. J . Med. 32, 1149-5 1.
CAUVIN J. F. (1815) Des bienfaits de l'insolation.
Paris.
FINSEN N.R. (1901) Phototherapy. London.
F~WATRICK T. B. & PATHAKM. A. (1959) Historical
aspects of methoxsalen and other furocoumarins. J .
Invest. Dermarol. 23, 229-31.
HARBER L. C. & BICKERS D. R. (1981) Phorosensiriv-
iry diseases. W. B. Saunders & Co., Philadelphia.
RAAB0. (1900) Ueber die Wirkung Fluorescierenden
Stoffe auf Infusorien. Z. Eiol. 39, 524-46.
VONTAPPEINER H. (1900) Ueber die Wirkung fluores-
cierenden Stoffe auf Infusiorien nach Versuchen von
0. Raab. Munch. Med. Wochenschr. 47, 5.
VONTAPPEINER H. & JESIONEKA. (1903) Therapeu-
tische Versuche mit fluorescierenden Stoffen.
Munch. Med. Wochenschr. 47. 2042-4.
VONTAPPEINER H. & JODLBAUER A. (1904) Ueber wir-
kung der photodynamischen (fluorescierenden)Stoffe
auf Protozoan und Enzyme. Drsch. Arch. Klin. Med.
80,427-87.
H. & JODLBAUER
A. (1907) Die Sen-
sibilisierende Wirkung Fluorescierender Substanzer.
Gasammerre Unter Suchungen Uber die Phorody-
namische Erscheinung. FCW Vogel, Leipzig.
JESIONEK A. & VONTAPPEINER H. (1905) Zur behand-
lung der Hautcarcinome mit fluorescierenden Stof-
fen. Arch. Klin. Med. 82. 223.
PRIME J. (1900) Les accidentes toxiques par I'eosinate
de sodium. Jouve & Boyer, Paris.
SCHERER H. ( 1841) Ann. d. Chem. u. Pharm. 40,I .
MULDER J. (1844) Prakt. Chem. 32, 186.
THUDICHUM J. L. (1867) Tenrh Report of the Medical
Officer ofrhe Privy Council. HM Stationery Office,
London.
HOPE-SEYLER F. (1871) Med. Chem. Untersuchungen.
pp. 124-528.
HAUSMANN W. (1908) Die sensibilisierende Wirkung
tierscher Farbstoffe und ihne physiologische Bedeu-
tung. Wien. Klin. Wochnschr. 21, 1527-9.
HAUSMANN W. (191 1) Die sensibilisierende Wirkung
des hamatoporphyrins. Eiochem. Zeir. XXX. 276-
316.
H. (191 I ) Der Nachweis photodynamischer
Wirkungen fluorescierenden Stoffe am levenden
Warmbluter. In: Handbuch der Eiochemischen (Ed.
E. Abderhaldan), pp. 563-71. Arbeitsmithoden,
Berlin.
F. (1913) Untersuchungen uber die
Biologische (photodynamische)Wirkung des hama-
toporphyrins und anderer Derivative des Blut-und Gal-
lenfarbstoffs. Drsch. Arch. Klin. Med. 112,476-503.
G. L., POH-FKZPATRICK M. & DROHN D. L.
(1973) Induction of drug photosensitisation in man
 PHOTODYNAMICTHERAPY
after parenteral exposure to haematoporphyrin. Arch.
Dermatol. 113, 1392-7.
26. FlsCHm H., HILMER H., LINDERF. & PlrrZER B.
(1925)Z.fhysiol. Chem. 150.44.
27. REMBORG R. & LEGGEI. W. (1949)Hematin Com-
pounds and Bile figments. Interscience Publishers
Inc., New York.
28. POLICARD A. (1924)Etude sur les aspects offerts par
des tumeurs experimentales examintes a la Iumihre
de Wood. C. R. SOC.Biol. 91,1423-8.
29. AULER H. & BANZER G. (1942)Untersuchungen iiber
die Rolle der Porphyrine bei geschwulstkranken
Menschen und Tieren. Z . Krebsforsch 53.65-8.
30. FIGGEF.H. J.. WEJIANDG. S.B~MANGANIEUOL. 0. J.
(1948)Cancer detection and therapy: Affinity of neo-
plastic, embryonic and traumatised tissues for por-
phyrins and metalloporphyrins. Proc. Soc. Exp.
Biol. Med. 68, 640- 1.
31. RASSMUSSEN-TAXDAL D. S., WARDG. E. & F m
F. M. 1. (1955)Fluorescence of human lymphatic
and cancer tissues following high doses of intra-
venous haematoporphyrin. Cancer 8,78-81.
32. SCHWARTZ S. K., ABSOLON K. & VERMUND H. (1955)
Some relationships of porphyrins, x-rays and
tumours. Univ. Minn. Med. Bull. 27,7-8.
33. LIPSONR. L. & BALDES E. J. (1960) The photody-
namic properties of a particular haematoporphyrin
derivative. Arch. Dermatol. 82,508-16.
34. LIPSON R. L., BALDES E. J. & OLSENA. M. (1%1)
The use of a derivative of haematoporphyrin in
tumour detection. J. Natl Cancer Inst. 26, 1-1 1.
35. LWSONR. L., BALDES E. 1. & OLSEN A. M. (1%1)
Hematoporphyrin derivative: A new aid for endo-
scopic detection of malignant disease. J. Thorac.
Cardiovasc. Surg. 42,623-9.
36. LIPSON R. L., BALDES E. J. & OLSENA. M. (1964)
Further evaluation of the use of haematoporphyrin
derivative as a new aid for the endoscopic detection
of malignant disease. Dis. Chest 46, 676-9.
37. LIPSONR. L., PRATTJ. H. & BALDES E. J. (1964)
Haematoporphyrin derivative for the detection of
cervical cancer. Obstet. Gynecol. 24, 78.
38. LIPSONR. L., BALDE~ E. J. & GRAYM. J. (1967)
Hematoporphyrin derivative for detection and man-
agement of cancer. Cancer 20,2255-7.
39. BERGH. & JUNGSTAND W. (1966) Photodynamische
wirkung auf das solide Ehrlich kaninom. Naturwiss
53,481.
40. JUNGSTAAD W. & BERGM. (1%7) In vivo Versuche
zur Cytostase durch photodynamische Effekte von
Redox farben. Studia Biophys. 3,225.
41. DIAMOND I., GRANELLI S. G.,MCDONAGH A. F.,
NIELSENS. F., WILSON C. B. & JAENICKE R. (1972)
Photodynamic therapy of malignant tumours. Lancet
U, 1175-7.
42. D~UGHERTY T. J. (1974) Activated dyes as anti
tumour agents. J. Nor1 Cancer Inst. 52, 1333.
43. THOMSON S. H., EMMETI E. A. & Fox S. H. (1974)
Photodestruction of mouse epithelial tumours after
oral acridine orange and argon laser. Cancer Res.
34.3124.
44. D~UGHERTY T. J.. GRINDEY
G. B., WEISHAUPT K. R. &
BOYLE D. G. (1975)Photoradiation therapy 11. Cure
of animal tumours with haematoporphyrin and light.
341
J. Natl CancerInst. 55. 115-21.
45. KFUY J. F., SNW M. E.& BERENBAUM M. C. (1975)
Photodynamic destruction of human bladder carci-
noma. Brit. J. Cancer 31,237-44.
46. DOUGHERTY T. J., K”J. E., GOLDFARB A.,
WEISHAUPT K. R., B o r n D. & M ~ I L E MA.A (1978)
N
Photoradiationtherapy for the treatment of malignant
tumours. Cancer Res. 38,2628-35.
47. BENSON R. C. JR, FARROW G . M., KINSEYJ. H., COR-
TESE D. A., ZINCKE H. & U n D. C. (1986)Detection
and localisation of in situ carcinoma of the bladder
with haematoporphyrin derivative. Mayo Clin. Proc.
57,548-55.
48. MISAZUMIH., MISAKIT. & MIYOSHIN. (1983)
Photodynamic therapy of bladder tumours. In: Lusers
and HaematopotphyrinDerivative in Cancer (EdsY.
Hayata & T. J. Dougherty), pp.85. Igaku-Shoin,
Tokyo.
49. JOCHAM D., STACHLER G.,CHAUSSY C. H., HANMER C.
& ~ H R U.S (1981) Laser bchandlung von Blasen-
tumoren nach photosensitibilisieng nit Haemato-
porphyrin Derivat. Urologe A 20,340.
50. HAYATA Y., K A H.,~ KONAKA C.. ONOJ. & TAKEAWA
N. (1982) Hematoporphyrin derivative and laser
photoradiation in the treatment of lung cancer. Chest
81,269-77.
D. R. & HUTHG.C.(1984)
0. J., DOIRON
51. BXLCHUM
Hpd photodynamic therapy for obstructing lung
cancer. In: forphyrin Localisation and Treatment of
Tumours (Eds D. R. Doiron & C. J. Gomer),
pp. 727-45.Alan R. Liss, New York.
52. CORTESED. A. & KINSEYJ. M. (1982)Endoscopic
management of lung cancer with haematoporphyrin
derivative phototherapy. Mayo Clin. Proc. 57,543.
53. AIDAM. & HIRASHIMA T. (1983) Cancer of the
oesophagus. In: Lasers and Haematopotphyrin Deriva-
tive in Cancer (Eds Y. Hayata & T. J. Dougherty),
p. 57. Igaku-Shoin Tokyo, New Yo&.
54. THOMASR. J., A e m M., BHATHAL P. S., ST JOHN
D. J. B. & MDRSTYN G. (1987)High dose photoradia-
tion of oesophageal cancer. Ann. Surg. 206, 193-9.
55. ADA M., KWAGUCHI M. (1983)Gastric cancer. In:
Lasers and Haematoporphyrin Derivative in Cancer
(Eds Y. Hayata & T. J. Dougherty), p.65. Igaku-
Shoin, Tokyo.
56. WILEA. G.,DAHLMAN A. & BURNSR. G. (1982)
Laser photoradiation therapy of cancer following
haematoporphyrin sensitisation. Lasers Surg. Med.
2. 163.
57. DOUGHERTY
T. J. (1984)An overview of the status of
photoradiation therapy. In: Porphyrin Localisation
and Treatment of Tumours (Eds D. R. Doiron &
C. J. Gomer), pp. 75-87. Alan R. Liss, New York.
58. FORBES I. J., COWLED P. A., LEONO A. S . Y. er 01.
(1980) Phototherapy of human tumours using hae-
matoporphyrin derivative. Med. J . Aust. 2,489-93.
59. WARDB. G.,FORBES1. J., COWLEDP. A., MCEVOY
M. M. &Cox L. W. (1982)The treatment of vaginal
recurrences of gynaecologic malignancy with
phototherapy following haematoporphyrin derivative
pretreatment. Amer. J. Obstet. Gynecol. 142,356.
60. Russo A. & MITCHELL J. B. (1990) Future directions
for photodynamic therapy. In: Phototherapy of
Cancer (Eds G . Morstyn & A. H. Kaye). H a n v d
348
Academic Publishers, Switzerland.
61. WILEA. G., NOVOTNY J., MASONG. R., PASSYV. &
BERNS M. W. (1984) Photoradiation therapy for head
and neck cancer. In: Porphyrin Localisation and
Treatment of Tumours (Eds D. R. Doiron & C. J.
Gomer), pp.681-91. Alan R. Liss, New York.
62. TAHETA C. & IMAHIIRE M. (1983) Cancer of ear, nose
and throat. In: Lasers and Haemaroporphyrin Deri-
vative in Cancer (Eds Y. Hayata & T. J. Dougherty),
p. 70. Igaku-Shoin, Tokyo.
63. MURPHEE A. L., COFEM. & GOMER C. J. (1987) The
evolution of photodynamic therapy in the treatment
of intraocular tumours. Photochem. Photobid. 46,
919-23.
64. BRUCE R. A. JR (1984) An approach to the treatment
of ocular malignant melanomas. In: Porphyrin
Localisation and Treatment of Tumours (Eds D. R.
Doiron & C. J. Gomer), pp. 777-84. Alan R. Liss,
New York.
65. LAWSE. R. JR,CORTESE D. A., KINSEYJ. H., EAGAN
R. T. & ANDERSON R. E. (1981)Photoradiation therapy
in the treatment of malignant brain tumours: A phase
I (feasibility) study. Neurosurgery 9, 672-8.
DANIELL AND HILL
66. MCCULLCCHG. A. J.. FORBESI. J., LEE S . K.,
COWLED P. A,, JACKAF. J. & WARDA. D. (1984)
Phototherapy in malignant brain tumours. In: Por-
phyrin Localisation and Treatment of Tumours (Eds
D. R. Doiron & C. J. Gomer), pp. 709-17. Alan R.
Liss, New York.
67. KAYEA. H., MORSTYN G. & BROWNBILL D. (1987)
Adjuvant high-dose photoradiation therapy in the
treatment of cerebral glioma: A Phase 1-2 study.
J . Neurosurg. 67. 500-5.
68. PERRIA C., CAPUZZO T., CAVAGNARO G. er al. (1980)
First attempts at the photodynamic treatment of
human gliomas. J . Neurosurg. Sci. 24, 119-29.
69. WHAREN R. E. JR, ANDERSON R. E. & LAWSE. R. JR
( 1983) Quantitation of haematoporphyrin derivative
in human gliomas, experimental central nervous sys-
tem tumours, and normal tissues. Neurosurgery 12.
446-50.
70. MULLER P. J . & WILSONB. C. (19%) Photodynamic
therapy of malignant brain turnours. Lasers Med.
Sci. 5, 245-52.
7 1. BONNETIR. (1989) A death ray for cancer? New
Scienrist. 28 Jan., 55-8.