Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Transferases
Patent
1995-04-24
1997-11-25
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Transferases
435232, A61K 3851, C12N 988
Patent
active
056909292
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to methods of anti-methionine chemotherapy using methioninase as an antitumor agent.
BACKGROUND
Therapeutic drug-based treatment of cancer is directed at the use of medicinals which selectively inhibit or kill the cancer cells while not harming normal tissue function beyond acceptable amounts. The difficulty with conventional chemotherapy has been the toxicity of therapeutic drugs for normal tissue.
Many tumors have been shown to have absolute requirement for methionine in a variety of cell types and evaluated tumor tissues, including tumors of the colon, breast prostate, ovary, kidney, larynx melanoma, sarcoma, lung, brain, stomach and bladder. Methionine dependence has been defined as an inability of tumors to grow when methionine is replaced by homocysteine in the growth medium. See, for example, Chello et al., Cancer Res., 33:1898-1904 (1973); and Hoffman, Anticancer Res., 5:1-30 (1985).
Methionine depletion has been shown to selectively synchronize methionine-dependent tumor cells into late S/G.sub.2 phase of the cell cycle. Hoffman et al, Proc. Natl. Acad. Sci. USA, 77:7306-7310 (1980). Using the combination of methionine deprivation, followed by repletion of methionine coupled with exposure to an antimitotic agent, termed anti-methionine chemotherapy, tumor cells have been selectively eliminated from co-cultures of normal and tumor cells, resulting in cultures of normal cells proliferating vigorously. Stern et al., J. Natl. Cancer Inst., 76:629-639 (1986).
However, in order for methionine-dependent chemotherapy to be conducted in vivo, it is necessary to have a means to effectively deplete serum of circulating methionine. Methionine depletion methods have not been described that reduce circulating methionine levels in vivo in a manner sufficient to be effective in anti-tumor therapies.
Methioninase, an enzyme which degrades methionine, has been purified from a variety of bacterial sources, and has been reported to slow the rate of tumor cell proliferation in vitro. Kreis et al., Cancer Res., 33:1862-1865, and 1866-1869 (1973); Tanaka et al., FEBS Letters, 66:307-311 (1976) Ito et al., J. Biochem., 79:1263-1272 (1976); and Nakayama et al., Agric. Biol. Chem., 48:2367-2369 (1984).
Kreis et al., Cancer Res., 33:1866-1869 (1973), have described the use of partially purified methioninase at 1150 units/kg/day to inhibit growth of carcinosarcoma cells implanted in a mouse model. Although the enzyme reduced primary tumor cell growth, it was not reported to reduce the T/C (treated versus control) ratio of tumor diameter below 50%, and was not reported to have any effect on metastasis. The authors also indicated that tumor specificity of the methioninase cannot be expected without other unspecified interventions, and further do not comment on the possible endotoxin content of a partially purified enzyme or its effect on mice. The only toxicity studies reported were absence of animal body weight loss after the duration of the treatment, and that negative gross examination for toxicity. Further, the authors report that the enzyme had a serum half life of 4 hours.
Kreis et al., Cancer Res., 33:1866-1869 (1973), further reported the use of a methionine-free diet as a means to deplete methionine as an anti-tumor therapy. However, the authors reported that the diet did not slow tumor growth as effectively as the use of methioninase and resulted in the undesirable side effect of continuous loss of weight of the animal. The authors did not report the use of methionine-deficient diets combined with methioninase treatment, and did not study cell synchronization.
There continues to be a need for an effective methionine-dependent chemotherapy of tumors directed at effectively reducing the amount of methionine as to provide a beneficial anti-tumor effect without deleterious injury.
BRIEF DESCRIPTION OF THE INVENTION
It has now been discovered that methioninase can deplete levels of methionine in mammals without harm, can be effectively used to selectively inhibit tumor
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Guo Huiyan
Han Qinghong
Lishko Valeryi
Tan Yuying
Xu Mingxu
Anticancer Inc.
Lau Kawai
Wax Robert A.
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