Recombinant blood products and therapeutic enzymes - Pharmaceutical Biotechnology: Concepts and Aapplications - page 358

Table 12.8 Enzymes used therapeutically

Enzyme Application

Tissue plasminogen activator Thrombolytic agent

Urokinase Thrombolytic agent

Ancrod Anticoagulant

Factor IXa Haemophilia B

Asparaginase Anti-cancer agent

Nuclease (DNase) Cystic fi brosis

Glucocerebrosidase Gaucher's disease

α-Galactosidase Fabry disease

Urate oxidase Hyperuricaemia

Laronidase Mucopolysaccharidosis

Superoxide dismutase (SOD) Oxygen toxicity

Acid α-glucosidase Pompe disease

Mucopolysaccharidosis I (MPS I)

α- L -Iduronidase

N -Acetylgalactosamine-4-sulfactase Mucopolysaccharidosis IV

Trypsin/papain/collagenase Debriding/anti-infl ammatory agents

Lactase/pepsin/papain/pancrelipase Digestive aids

Most healthy (untransformed) mammalian cells are capable of directly synthesizing asparagine
from glutamine (Figure 12.14). Hence, asparagine is generally classifi ed as a non-essential amino
acid (i.e. we do not require it as an essential component of our diet). However, many transformed
cells lose the ability to synthesize asparagine themselves. For these, asparagine becomes an es-
sential amino acid. In the case of the leukaemic mice, the guinea pigs' asparaginase deprived
the transformed cells of this amino acid by hydrolysing plasma asparagine. This approach has
been successfully applied to treating some forms of human leukaemia. For example, the PEG- L -
asparaginase previously mentioned was approved for the treatment of refractory childhood acute
lymphoblastic leukaemia.
Generally, the plasma concentration of asparagine is quite low (~40 mol l 1 ). Therefore, thera-

peutically useful asparaginases must display a high substrate affi nity (i.e. low K m values). As-
paraginase from E. coli and Erwinia , as well as from Pseudomonas and Acinetobacter , has been
studied in greatest detail. It has proven effective in inhibiting growth of various leukaemias and
other transformed cell lines. PEG-coupled enzymes are often preferred, as they display an ex-
tended plasma half-life.
Although asparaginase therapy has proven effective, a number of side effects have been associ-
ated with initiation of therapy. These have included severe nausea, vomiting and diarrhoea, as well
as compromised liver and kidney function. Side effects are probably due to a transient asparagi-
nase defi ciency in various tissues. Under normal circumstances, dietary-derived plasma asparag-
ine levels are suffi cient to meet normal tissue demands, and the cellular asparagine biosynthetic
pathway remains repressed. Reduced plasma asparagine levels result in the induction of cellular
asparagine synthesis. High-dose asparaginase administration will immediately reduce plasma as-
paragine levels. However, the ensuing initiation of cellular asparagine synthesis may not occur for
several hours. Thus, a more suitable therapeutic regimen may entail initial low-dose asparaginase
administration, followed by stepwise increasing dosage levels.

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