54
for anti-cancer therapy where depletion and thereby the induction of starvation of
amino acids is attained in tumour cells which are auxotrophic to particular amino
acids. This often reduces tumour proliferation. Enzyme prodrug therapy uses
antibody- conjugated enzymes, converting prodrug into cytotoxic drug at tumour
cells and thereby killing tumour cells.
2.3.1 Antineoplastic Enzyme Therapy
2.3.1.1 L-asparaginase
L-aspraginase is a widely used antineoplastic enzyme, and it is involved in the
hydrolysis of L-asparagine to aspartate and ammonia. L-asparaginase is one of the
most potent therapeutic agents against acute lymphoblastic leukaemia (ALL).
Reduction of lymphomas was observed when administered with guinea pig serum
in mice and it was later found that it was due to L-asparaginase. Tumour cells often
depend on circulating L-asparagine for their survival as they lack the ability to synthesize L-asparagine, whereas normal cells with the help of L-asparagine synthetase
produce the amino acid. L-asparaginase readily upon administration converts the
circulating L-asparagine available. This makes tumour cells starved for the amino
acid and eventually prevents cell proliferation. L-asparaginase was known to be
isolated from various sources such as bacteria, fungi, plants and animals. Plant
sources include Pisum sativum, Withania somnifera, etc. L-aspraginase has also
been isolated from pancreas, spleen and kidneys of many animals. Bacterial producers include Erwinia chrysanthemi, Escherichia coli, Serratia marcescens, Proteus
vulgaris, Vibrio succinogenes, etc. Pegasparagase enzyme (asparaginase complexed
with polyethylene glycol (PEG) has a better half-life, increased stability and is safer
for patients with allergy to native enzyme (Kurtzberg et al. 2011). Elspar
®
and
Oncaspar
®
(Pegasparagase) are two commercially available forms of L-asparaginase.
Oncaspar
®
received USFDA approval in 2006 for treatment of ALL (Fig. 2.6).
2.3.1.2 Arginine Deaminase
Another antineoplastic enzyme therapy is by arginine deprivation of cancer cells.
Arginine is a non-essential amino acid synthesized by argininosuccinate synthetase
(ASS) and argininosuccinate lyase from citrulline. In normal cases cells do not
require arginine supply. But certain cancer cells lack ASS such as melanoma, renal
cell carcinomas and hepatocellular carcinomas and they require circulating arginine. Arginine deiminase (ADI) is an enzyme from mycoplasma that converts arginine to citrulline, thereby reducing circulating arginine. This causes arginine
deprivation in tumour cells that lack argininosuccinate synthetase, thereby inhibiting tumour progression (Kim et al. 2009). ADI itself is antigenic and enzyme ADI
can be modified by attaching polyethylene glycol (PEG) (ADI-PEG 20) to reduce
antigenicity and improve half-life. ADI-PEG20 was found to be effective for hepatocellular carcinoma, malignant melanoma and pancreatic cancer cells (Ensor et al.
2002) (Fig. 2.7).
S.S. Kumar and S. Abdulhameed
for anti-cancer therapy where depletion and thereby the induction of starvation of
amino acids is attained in tumour cells which are auxotrophic to particular amino
acids. This often reduces tumour proliferation. Enzyme prodrug therapy uses
antibody- conjugated enzymes, converting prodrug into cytotoxic drug at tumour
cells and thereby killing tumour cells.
2.3.1 Antineoplastic Enzyme Therapy
2.3.1.1 L-asparaginase
L-aspraginase is a widely used antineoplastic enzyme, and it is involved in the
hydrolysis of L-asparagine to aspartate and ammonia. L-asparaginase is one of the
most potent therapeutic agents against acute lymphoblastic leukaemia (ALL).
Reduction of lymphomas was observed when administered with guinea pig serum
in mice and it was later found that it was due to L-asparaginase. Tumour cells often
depend on circulating L-asparagine for their survival as they lack the ability to synthesize L-asparagine, whereas normal cells with the help of L-asparagine synthetase
produce the amino acid. L-asparaginase readily upon administration converts the
circulating L-asparagine available. This makes tumour cells starved for the amino
acid and eventually prevents cell proliferation. L-asparaginase was known to be
isolated from various sources such as bacteria, fungi, plants and animals. Plant
sources include Pisum sativum, Withania somnifera, etc. L-aspraginase has also
been isolated from pancreas, spleen and kidneys of many animals. Bacterial producers include Erwinia chrysanthemi, Escherichia coli, Serratia marcescens, Proteus
vulgaris, Vibrio succinogenes, etc. Pegasparagase enzyme (asparaginase complexed
with polyethylene glycol (PEG) has a better half-life, increased stability and is safer
for patients with allergy to native enzyme (Kurtzberg et al. 2011). Elspar
®
and
Oncaspar
®
(Pegasparagase) are two commercially available forms of L-asparaginase.
Oncaspar
®
received USFDA approval in 2006 for treatment of ALL (Fig. 2.6).
2.3.1.2 Arginine Deaminase
Another antineoplastic enzyme therapy is by arginine deprivation of cancer cells.
Arginine is a non-essential amino acid synthesized by argininosuccinate synthetase
(ASS) and argininosuccinate lyase from citrulline. In normal cases cells do not
require arginine supply. But certain cancer cells lack ASS such as melanoma, renal
cell carcinomas and hepatocellular carcinomas and they require circulating arginine. Arginine deiminase (ADI) is an enzyme from mycoplasma that converts arginine to citrulline, thereby reducing circulating arginine. This causes arginine
deprivation in tumour cells that lack argininosuccinate synthetase, thereby inhibiting tumour progression (Kim et al. 2009). ADI itself is antigenic and enzyme ADI
can be modified by attaching polyethylene glycol (PEG) (ADI-PEG 20) to reduce
antigenicity and improve half-life. ADI-PEG20 was found to be effective for hepatocellular carcinoma, malignant melanoma and pancreatic cancer cells (Ensor et al.
2002) (Fig. 2.7).
S.S. Kumar and S. Abdulhameed