Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-06-07
1998-03-24
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514262, A61K 3133, A61K 3152
Patent
active
057313040
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Temozolomide, or 81045, NSC 362856) has been found to possess valuable antitumour properties, see Newlands et al., Br. J. Cancer, 65: 287 (1992). In the clinic, temozolomide has shown activity against astrocytoma, gliomas, malignant melanoma and mycosis fungoides. The drug is most useful when administered according to a repeat dose schedule.
Methylated O.sup.6 -alkylguanine, e.g., from reaction with MTIC (the active methylating species of temozolomide), is repaired by the protein O.sup.6 -alkylguanine DNA alkyltransferase (ATase). Pretreatment of ATase-expressing cells with methylating agents (e.g., Zlotogoski et al., Carcinogenesis, 5:83, 1984; Gibson et el., Cancer Res., 46:4995, 1986), O.sup.6 -methylguanine (e.g., Dolan et al., Biophys. Res. Commun., 132:178 1985) or O.sup.6 -benzylguanine (O.sup.6 -BG, Dolan et al., Proc. Natl. Acad. Sci. U.S.A., 87:5368, 1990) has thus been shown to increase the cytotoxic effects of chloroethylating agents whilst little or no sensitization was observed in cells that do not express ATase.
Moschel, Dolan and Pegg, in U.S. Pat. No. 5,091,430, note that a transient decrease in ATase activity is all that is needed to enhance the effectiveness of chloroethylating agents. PCT published Application WO 91/13898 notes, for instance, a 3.8 fold decrease in the ED.sub.50 for Me CCNU when combined with O.sup.6 -benzylguanine in SF767 cells. Thus, Moschel et al. show a general enhancement of the anti-neoplastic activity of an alkylating agent when used with a depletor of alkyltransferase.
Applicants' invention, which is surprising and unobvious in view of the earlier work, is that the chemotherapeutic effects of temozolomide can be dramatically potentiated (up to 300-fold for the MAWI cell line) by utilizing a particular dosing regimen which incorporates the administration of an ATase inhibitor. Thus, human cell cancers which were heretofore insusceptible or only mildly susceptible to temozolomide therapy can be treated by the combination of temozolomide with an ATase inhibitor.
Accordingly, it is a principal object of the present invention to provide compositions and methods for improving and extending the therapeutic usefulness of temozolomide as an antineoplastic agent by a combination therapy with a potentiator which is an inhibitor of the enzyme O.sup.6 -alkylguanine DNA alkyltransferase (ATase).
It is a further object of the present invention to provide therapeutic regimens using these compositions and methods for the optimal potentiation of toxicity of temozolomide to human cancer cells.
It is a still further object of the present invention to provide a repeat dosing regimen of temozolomide which is potentiated by prior or concomitant administration of an ATase inhibitor.
It is a still further object of the present invention to provide a method of determining the relative potentiation of temozolomide toxicity by an ATase inhibitor of a particular human cancer cell by ascertaining the amount of ATase produced by said cancer cell.
SUMMARY OF THE INVENTION
The present invention relates to the potentiation of temozolomide toxicity in human cancer cells using inhibitors of O.sup.6 -alkylguanine DNA alkyltransferase (ATase). Further, a dosage regimen for optimal therapy, and methods of identifying potentially temozolomide-sensitive human cancer cells, are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of the cytotoxicity (IC.sub.50) of temozolomide (.box-solid.) and CCNU (x) versus cellular Atase levels in the human tumour cell lines (in order of increasing ATase levels): ZR-75-1, U87MG, U373, LS174T, LOVO, MCF-7 and MAWI.
FIG. 2 is a graph of the cytotoxicity of temozolomide in pZipneoSV(X) 1-transfected (.smallcircle.,.box-solid.) or phAT-transfected (.tangle-soliddn.,.tangle-solidup.)XP-derived cell lines in the presence (.box-solid.,.tangle-solidup.) or absence (.smallcircle.,.tangle-soliddn.) of 10 .mu.M BG. Error bars indicate +/-1 s.d.
FIG. 3 is a graph of the cytoxicity ratio of repeated daily doses of temozolomide in MAWI
REFERENCES:
patent: 4536386 (1985-08-01), Keenan
patent: 5091430 (1992-02-01), Moschel et al.
patent: 5260291 (1993-11-01), Lowt et al.
Dolan, M.E. et al., "Comparison of the inactiviation of mammalian and bacterial O.sup.6 -alkylguanine-DNA alkyltransferases by O.sup.6 -benzylguanine and O.sup.6 -methylguanine", Carcinogenesis, 12(12):2305-9 (1991).
Dolan, M.E. et al., "Effect of O.sup.6 -benzylguanine analogs on O.sup.6 -alkyltransferase activity and on the sensitivity of cells to alkylating agents", Proc. Annu. Meet Am. Assoc. Cancer Res., 32:A2227 (1990).
Moshel, R.C. et al., "Structural Features of Substituted Purine Derivatives Compatible wIth Depletion of Human O.sup.6 -Alkylguanine-DNA Alkyltransferase", J. Med. Chem., 35(23):4486-91 (1992).
Gonzaga, P.E. et al., "Evidence that covalent complex formation between BCNU-treated oligonucleotides ad E. coli alkyltransferases requires the O.sup.6 -alkylguanine function", Nucleic Acids Res., 18(13):3961-6 (1990).
Gonzaga, P.E. et al., "Formation of a covalent complex between BCNU-treated oligodeoxynucleotides and E. coli DNA alkyltransferase does not include the phosphotriester repair function", Proc. Annu. Meet Am. Assoc. Cancer Res., 31:A14, (1990).
Hammdan, M.A. et al., "Depletion of O.sup.6 -Alkylguanine-DNA alkyltransferase by O.sup.6 -benzylguanine in three-dimensional collagen cultures of normal human breast epithelial cells", Carcinogenesis, 13(10):1743-9 (1992).
Silber, J.R. et al., "O.sup.6 -Alkylguanine DNA-alkyltransferase is Not a Major Determinant of Sensitivity to 1,3-Bis(2-chloroethyl)-1-nitrosourea in Four Medulloblastoma Cell Lines", Oncol. Res., 4(6):241-8 (1992).
Gerson, S.L. et al., "Modulation of Nitrosourea Resistance in Human Colon Cancer by O.sup.6 -Methylguanine", Biochem. Pharmacol., 43:1101-7 (1992).
Bronstein, S.M. et al., "Efficient Repair of ).sup.6 -Ethylguanine, but not O.sup.4 -Ethylthymine or O.sup.2 -Ethylthymine, Is Dependent upon O.sup.6 -Alkylguanine-DNA Alkyltransferase and Nucleotide Excision Repair Activities in Human Cells", Cancer Res., 52(7):2008-11 (1992).
Pegg, A.E. et al., "Repair of DNA containing O.sup.6 -alkylguanine", FASEB J., 6(6):2302-10 (1990).
Lunn, J.M. et al., "Correlation between chemosensitivity of CB10-277 and O.sup.6 -alkyl-guanine-DNA alkyltransferase levels in human melanoma xenografts", Br. J. Cancer, 62(3): 514 (1990).
Hamdan, M.A. et al., "Depletion of O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) activity of O.sup.6 -methylguanine and O.sup.6 -benzylguanine in collagen-cultured human breast epithelial cells", Proc. Annu. Meet Am. Assoc. Cancer Res., 33:A22 (1992).
Gersch, S.L. et al., "Inactivation of alkyltransferase by O.sup.6 -benzylguanine reverses BCNU resistance in a human colon cancer xenograft", Proc. Annul. Meet Am. Assoc. Cancer Res., 32:A2233 (1991).
Dolan, M.E. et al., "Depletion of O.sup.6 -Alkylguanine DNA Alkyltransferase (AGT) by Treatment of O.sup.6 -Benzylguanine (BG).", Proc. Annu. Meet Am. Assoc. Cancer Res., 31:A2682, (1990).
Dexter, E.U. et al., "Modulation of O.sup.6 -Alkylguanine-DNA Alkyltransferase in Rats following Intravenous Administration of O.sup.6 -Methylguanine", Cancer Res., 49(13:3520-4 (1989).
Schold, S.C., Jr. et al., "O.sup.6 -Alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts", J. Neurosurg., 70(4):573-7 (1989).
Gerson, S.L. et al., "Inactivation of O.sup.6 -alkylguanine-DNA alkyltransferase in human colan cancer: a model for biochemical modulation of tumor drug resistance", Proc. Annu. Meet. Am. Assoc. Cancer Res., 30:A2271 (1989).
Taverna, P. et al., "Influence of o-methylguanine on DNA damage cytotoxicity of temozolomide in L1210 mouse leukemia sensitive and resistant to chloroethylnitroxoureas":, Anticancer Drugs, 3(4): 401-5 (1992).
Dolan, M.E. et al., "Effect of O.sup.6 -benzylguanine on the sensitivity of human tumor xenografts to BCNU", Proc. Annu. Meet Am. Assoc. Cancer Res., 33:A2895 (1992).
Gorbacheve, L.B. et al., "O.sup.6 Methylguanine A
Baer John Colin
Freeman Azadeh Alison
Margison Geoffrey Paul
Newlands Edward Stuart
Rafferty Joseph Anthony
Cancer Research Campaign Technology
Goldberg Jerome D.
LandOfFree
Potentiation of temozolomide in human tumour cells does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Potentiation of temozolomide in human tumour cells, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Potentiation of temozolomide in human tumour cells will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2289081