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The cancer therapeutic strategies known to date are not adequate for all cancer patients. Most of them are followed by a high rate of side effects and complications. The L-tryptophan depletion bioreactor is described as a possible new method of cancer therapy. L-tryptophan is an essential amino acid which has been recognized as an important cancer nutrient and its removal can lead to destruction of the tumour. Normal human cells or tumor cells cannot synthesize L-tryptophan and therefore tumor resistance is unlikely to develop. L-tryptophan is also a constituent for different bio-molecules such as Serotonin, Melatonin, and is needed for other synthesis processes in the cell growth. A column which contained TSO as a bioreactor was integrated in a plasmapheresis unit and tested it in different animals. Brest cancer and medulloblastoma showed the greatest efficacy of L-tryptophan degrading. Tryptophan side chain oxydase (TSO) is developed to treat cancer diseases successfully, and has low side effects. A combination of L-tryptophan depletion with all available cancer therapies is possible.
Keywords: L-tryptophan; Tryptophan side chain oxydase (TSO); TSO depletion bioreactor
Approximately 10% of all malignant diseases in a progressive stage can be cured. A great problem of the most administered chemotherapy regimens is often a development of resistance against different cancers [1,2]. In many cases the resistance exists primarily before the chemotherapy is administered, or the oncogenes of cancer cells can be mutated during the chemotherapy.
The end result is a resistance against the administered chemotherapy
A. A comparable mechanism is observed for the new kinase inhibitors. The cancer cells can change their oncogenes by mutations resulting in resistance against the kinase inhibitors. In these cases new drugs and therapeutic concepts must be developed continuously which are very expansive. In the last years various new sophisticated therapeutic strategies were developed of which some are summarized in Table 1 [3-12]. All the previous cancer therapeutic strategies are not effective in all patients and they are often associated with a high rate of side effects.
B. The high rate of side effects and low effectiveness need the development of new drugs and new therapeutic methods constantly. Various authors reported possibilities of treatment of different cancers with so-called anti-tumor
enzymes, bioreactors, as an extracorporeal tumor treatment
[13-15]. One possibility is the influence of the protein synthesis by depletion of essential amino acids such as L-Tryptophan [15-18].
The use of serum amino depletion as an effective anticancer agent was first published by Kidd [19,20]. He reported that serum of normal guinea pig could induce regression in certain
types of animal lymphomas. Subsequently, in 1961 Broome 
showed that the enzyme L-asparaginase was the anti-neoplastic
substance in normal guinea pig serum which depleted the serum
of the nonessential amino acid L-asparaginase. The principle of
removing amino acids from blood as a form of cancer therapy
has proven to be beneficial in cases of acute lymphoblastic
leukemia using L-asparaginase to degrade the nonessential
amino acid L-asparaginase, constituting an important tumor
nutrient. However, L-asparaginase sensitive tumours can
eventually become L-asparaginase resistant. This is usually
due to the increased denovo synthesis of L-asparaginase by
the tumor cells. L-asparaginase is a non-essential amino acid
and can be synthesized by the human organism. Roberts et al.
[14,22] described the isolation of the L-tryptophan degrading
enzyme, indolyl-3-alkane-α-hydroxylase, later shown to consist
of 2 isoenzymes and called tryptophan side chain oxydase (TSO
1, 2). Blood tryptophan depletion by TSO resulted in a significant
anti-neoplastic activity against mouse tumours in vivo.
Treatment of certain tumours by deprivation of the essential
amino acid L-tryptophan has the advantage over non-essential
amino acid deprivation, because tumor cells cannot synthesize
L-tryptophan [23,24]. This offers the potential advantage over
non-essential amino acid deprivation because host and tumour
cells cannot synthesize L-tryptophan, and tumour resistance is
therefore unlikely to develop. L-tryptophan cannot be produced
by human or animal cells itself. L-tryptophan is an essential
amino acid. L-tryptophan is an important amino acid for the
cellular integrity. L-tryptophan is needed for a lot of different
The exposure of tumor cells to decreased levels of the
essential amino acid L-tryptophan offers a potential advantage
in tumour treatment, since de novo synthesis cannot occur,
therefore preventing tumour resistance. Tumour cells sensitive
to L-tryptophan depeltion would repeatedly respond to this
form of therapy in contrast to all chemotherapeutic approaches
where resistance develops leading to the death of the patients.
L-tryptophan is an essential amino acid. A removal of this
nutrient from blood cannot overcome by a higher production in
the cells, therefore making it possible to treat sensitive tumor
cells over and again without the disadvantage of the tumor
being able to overcome the “bottle neck” situation of nutrient
To design a so-called bioreactor for removing the potential
cancer nutrient L-tryptophan from blood, the L-tryptophan
degrading enzyme tryptophan side chain oxidase 3 (TSO 3)
was isolated by Gottfried Schmer  and chemically bound to
Glutaraldehyd activated gamma amino silane silica and to Zeta
affinity micro-columns consisting of a Glutaraldehyd activated
polyacrylic-cellulose copolymer. In animal experiments a closed
circuit bioreactor in a single pass used. Zeta affinity bioreactors
degraded L-tryptophan levels changed little throughout the
experiment indicating a vast extra vascular tryphophan pool.
The procedures were tolerated well by the animals without any
change in vital signs. The TSO-was tested in sheep and rabbits
by Schmer  with a closed circuit mini plasmapheresis unit.
He could show that the L-tryptophan depletion in plasma was
100 % in sheep and 95% in rabbits by a single pass through
the bioreactor. The investigations in immune supprimized rats
with tumor like medullonblastoma were in 9/10 animal a strong
regression of the tumor in comparison to the control animals.
In 20 different tumor cell lines there were some different
results. Breast cancer and medulloblastoma showed the greatest
efficacy of L-tryptophan degrading. With gamma-interferon all
cell lines showed a higher L-tryptophan use and therefore a
rapid destruction of all cells.
Enzymatic removal of L-tryptophan from blood of a patient
by plasmapheresis and extracorporeal treatment by enzymatic
degradation of L-tryptophan in the pheresed blood has long
been perceived to have therapeutic benefits. For example, blood
levels of L-tryptophan modulate synthesis and synaptic release
of the neurotransmitter serotonin. Varying L-tryptophan blood
levels provides a means to affect brain serotonin levels. The
metabolites which are producing by the L-tryptophan degrading
enzymes will be eliminated by the human kidneys.
To treat the cancer successful, a new cancer therapy
consisting of the L-tryptophan degrading enzyme, TSO 3, has
been developed, which will be won by gene technology from
bacterial or fungal sources, TSO. The bioreactor based on Silica.
The amino groups containing silica beats were activated with
Glutaraldehyd. The activated aminosilane containing silica beats
were then washed after different procedures. The activated silica
beads can be stored in buffer at 4 °C and remain fully active for
more than 6 weeks. 20 to 30ml of the activated beads filled in a
column, sterilised and inserted in the filtrate line of an apheresis
unit. Advantages of the L-tryptophan degrading enzyme TSO
3 are an excellent stability, no development of a resistance to
tumor cells and the combination on this new therapy with all
other therapy measures especially with gamma interferon .
The production of the TSO 3 enzyme by gene technology,
production of the columns and sterilization is the first step,
than the new cancer therapy could be started in a clinical trial
with an apheresis unit after the revised Declaration of Helsinki
in different countries. The treatment of 1 circle includes 5-6
treatments per week, daily treatment time 4 to 5 hours and 3
to 4 weeks. The duration of a minimum of 4 hours per day is
necessary to keep the L-tryptophan concentration in the blood
as low as possible to release L-tryptophan from the vulnerable
cells of the tumor. The duration of 1 circle is 4 weeks because
a longer treatment can be influenced the L-tryptophan of the healthy organs. Another circle can be started again after 2 to 3
months, if no remission is reached. A combination with other
cancer therapies is possible. But 1 circle must be sufficient to
reduce the tumor and the metastases and reaches a remission.
Side effects are very low and are a serotonin deficiency like
anxiety, fatigue, cognitive impairment, agitation, chronic pain,
feeling worse etc, and side effects due to the extracorporeal
blood circulation . A further point is the toxicity of TSO.
This point must be clarified with different washing procedures
before the introduction of this therapy in humans. Endo-toxins
are available only won by Pseudomonas sources. They can
be eliminated by different washing procedures or by the gene
technology from fungal sources.
For example in Germany alone 400,000 to 480,000 women
and men afflict by different cancers per year. Of these patients,
20% to 30% die in the first year after diagnosing of the cancer.
The therapeutic measures to date have very different results in
view point of healing or quality of life, etc. The treatment costs
for one therapeutic cycle of L-tryptophan depletion of 3 to 4
weeks depend on the production costs of the column. The costs
for 15 to 20 primary separation of the blood and the perfusion of
plasma through the bioreactor column are comparable with the
costs of the immuno-adsorption. The costs can be reduced by
producing TSO from fungal sources and a treatment set of one
column for 3-4 weeks per patient and one treatment cycle. If only
0.1%-1% of the new patients who afflict the disease every year
will be treated, this would be a great benefit for the patients. The
treatment could be repeated after 2 to 3 months or more, if no
remission is reached by the first treatment cycle. Between the
cycles a staging of the cancer is necessary. A further step could
be the development of a direct blood perfusion, and a further
important step could be the development of a drug of TZSO 3 for
intravenous and/or oral application.