DNA coding for mammalian L-asparaginase

Details DNA coding for mammalian L-asparaginase DNA coding for mammalian L-asparaginase

1999-05-11

2001-08-14

Nashed, Nashaat T. (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

C435S252300, C435S252330, C435S320100, C536S023200, C536S023500

Reexamination Certificate

active

06274367

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel DNA which codes for L-asparaginase, and more particularly, to a DNA which codes for mammalian L-asparaginase.
2. Description of the Prior Art
L-Asparaginase (EC 3.5.1.1), an amidohydrolase which releases L-aspartic acid and ammonia when it acts on L-asparagine, is an enzyme which plays a major role in the metabolism of L-asparagine in plants, animals and microorganisms, and it has been energetically studied on its actual use as an antitumor agent since John G. Kidd had reported the inhibitory activity of L-asparaginase on lymphoma in “
The Journal of Experimental Medicine
”, Vol.98, pp.565-583 (1953). As a result, an L-asparaginase from
Escherichia coli
is now used as a therapeutic agent for leukemia and lymphoma.
However, the aforesaid L-asparaginase with a satisfactory antitumor activity is only an external protein for humans, and the administration of conventional compositions containing the L-asparaginase to patients frequently causes serious side effects such as hyperergy including anaphylaxis shock, urticaria, edema, wheeze and dyspnea. Therefore, these compositions are inevitably restricted in their administration doses and frequencies-by a large margin, and some proposals to reduce or even diminish such side effects have been made.
As a first proposal, Japanese Patent Laid-Open No.119,082/79 discloses an L-asparaginase from
Escherichia coli
which is chemically modified by blocking at least 65% of the amino acids of the L-asparaginase with 2-O-substituted polyethylene glycol-4,6-dichloro-S-triazine. As a second proposal, Japanese Patent Laid-Open No.320,684/92 discloses a human L-asparaginase which is obtained from a culture of fibroblasts from human lung, stomach or breast. The first proposal has the advantage that it can use an L-asparaginase from
Escherichia coli
which is readily preparable on an industrial scale, and has the disadvantage that the control of the modification reaction is difficult and the side effects could not be eliminated. The second proposal has the advantage that, unlike the L-asparaginase from
Escherichia coli
, human L-asparaginase does not substantially induce antibodies even when administered to patients, and has the disadvantage that the productivity of human fibroblasts is not sufficient as disclosed in Japanese Patent Laid-Open No.320,684/92, so that a relatively large-scale cultivation is inevitable to obtain a satisfactory amount of L-asparaginase.
Recently, recombinant DNA technology has made remarkable progress. Now, even a polypeptide with an incomplete elucidation of its amino acid sequence can be readily prepared in a desired amount, if only a gene coding for the polypeptide is once isolated and decoded for its nucleotide sequence, by preparing a recombinant DNA having a DNA which codes for the polypeptide, introducing the DNA into microorganisms or cells of animals or plants to obtain transformants, and then culturing the transformants.
In view of the foregoing, a gene coding for a mammalian L-asparaginase, preferably, the isolation of a gene coding for human L-asparaginase and the prompt elucidation of its base sequence have been in great demand in this field.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a DNA coding for mammalian L-asparaginase, and the present inventors attained this object by isolating a DNA coding for mammalian L-asparaginase, which is characterized in that it contains nucleotide sequences for either or both amino acid sequences of SEQ ID NOs:1 and 2, as well as in that it is hybridizable with any or all of DNAs with respective nucleotide sequences of SEQ ID NOs:3 to 5.


REFERENCES:
patent: 4-320684 (1992-11-01), None
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Kidd, John G., “Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum.” The Journal of Experimental Medicine, vol. 98, pp. 565-583 (1953).
Sambrook, J. et al., “Molecular Cloning, A Laboratory Manual.” 2nd Edition, pp. xi-xxxviii (1989).
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