Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1999-03-19
2003-06-24
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C424S085100, C424S085200, C514S002600, C514S034000
Reexamination Certificate
active
06582690
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for tumor treatment with cytokines, the monitoring of multidrug resistance (MDR)-associated genes and subsequent treatment with cytotoxic substances, as well as the use of these substances for producing a drug.
BACKGROUND
Efficiency of chemotherapy of malignant diseases is often limited by the simultaneous resistance towards structurally and functionally unrelated cytotoxic compounds. This multidrug resistance (MDR) phenomenon is mediated by MDR-associated genes such as mdr1, MRP (MDR-associated protein) and/or LRP (lung resistance protein). The classical resistance type of MDR is caused by overexpression of the mdr1 gene product, the P-glycoprotein (Pgp) (U. A. German et al., Sem. Cell. Biol. 4, (1993):63-76). In normal tissues Pgp expression has been detected mainly in epithelial cells with excretory or secretory function (A. T. Fojo et al., Proc. Natl. Acad. Sci. USA,84 (1987):265-269). In tumors of almost every localization, including in brain tumors, expression of the mdr1 gene has been observed (K. Nooter et al., Br. J. Cancer 63 (1991):663-669 and M. Mousseau et al., Eur. J. Cancer (1993):753-759). There exist a number of different approaches for the so-called reversal or overcoming of MDR that are mainly based on the inhibition of Pgp as drug-efflux-pump, but that also imply toxic side effects (J. Kellen, Anticancer Res. 13 (1993):959-961). Calcium channel blockers, alkaloids, Pgp-specific antibodies etc. are among these resistance modifying agents.
W. Walther and U. Stein describe in J. Cancer Research and Clinical Oncology (W. Walther et al., J: Cancer Res. Clin. Oncol. 120 (1994):471-478) and in British Journal of Cancer (U. Stein et al., Br. J. Cancer.47 (1996):1384-1391) the influence of cytokines on mdr1 expression in human colon carcinoma cell lines. It has been found, that 48 hours and 72 hours detectable reduction in mdr1 expression can be seen after cytokine treatment. The cell lines LoVo, SW480, LS174T, HCT15 and HCT116 were used for these experiments. TNF&agr;, IFNy and IL-2 were utilized as cytokines. Vincristine and doxorubicin were used as cytostatic substances. The cytokine-mediated effects on mdr1 gene expression, associated with chemosensitization, have also been shown for the gene transfer of TNF&agr; into human U373 MG glioblastoma cells (W. Walther et al. Int. J. Cancer (1995):832-hours and 72 hours after cytokine treatment detectable reduction in mdr1 expression can be seen. The cell lines LoVo, SW480, LS174T, HCT15 and HCT116 were used for these experiments. TNF&agr;, IFNy, and IL-2 were utilized as cytokines. Vincristine and doxorubicin were used as cytostatic substances. The cytokine-mediated effects on mdr1 gene expression, associated with chemosensitization, have also been shown for the gene transfer of TNF&agr; into human U373 MG glioblastoma cells (W. Walther et al. Int. J. Cancer (1995):832-8 839). It has been pointed out in agreement with other authors (e.g. C. H. Evans et al. Cancer Res. 52 (1992):5893-5899 and K. E. Sampson et al. Cancer Lett. 68 (1993):7-14), that modulation of mdr1/Pgp expression is an interesting alternative to conventional therapies for MDR reversal. A suitable procedure for this is neither proposed nor suggested.
DESCRIPTION OF THE INVENTION
It is an object of the present invention to provide a process for modulation of mdr1/Pgp expression. Using this process tumors can be treated, which until now were not or only minimally susceptible such a therapy with certain MDR-associated cytotoxic substances in chemotherapy. Thus, colorectal carcinomas would, in contrast to previous therapies with antimetabolites, be better susceptible therapies with MDR-associated cytostatics such as vinca alkaloids and/or anthracyclines.
The invention utilizes a cytotoxic, MDR-associated substance for the generation of a therapeutic for tumor therapy by chemosensitization of tumor cells of a cancer patient with a cytokine, the determination of the level of one or several MDR-associated genes (e.g. mdr1, Mrp, Lrp) in the tumor tissue of the patient in dependence on the start of the cytokine treatment, the determination of the time period during which the expression of one or several MDR-associated genes is considerably reduced by the cytokine treatment, the treatment of the patient during the determined time period (“therapeutic window”) with a therapeutically effective amount of a cytotoxic, MDR-associated substance, which is influenced (improved) in its efficacy by the expression of one or several MDR-associated genes.
Another object of the invention is a process for tumor therapy of patients with a MDR-associated cytotoxic substance, chemosensitization of tumor cells of a patient by cytokines, the determination of the level of one or more MDR-associated genes (e.g. mdr1, Mrp, Lrp) in the tumor tissue of the patient in dependence on the start of the cytokine treament, determination of the time period during which the expression of one or several MDR-associated genes is considerably reduced by the cytokine treatment, the treatment of the patient at the determined time period (“therapeutic window”) with a therapeutically effective amount of a cytotoxic, MDR-associated substance, which is influenced (improved) in its efficacy by the expression of one or several MDR-associated genes.
Thus, as used throughout the disclosure and the claims, “therapeutic window” means the patient-specific time period during which the expression of one or more MDR-associated genes is substantially reduced by the treatment with cytokine.
It was surprisingly found that after treatment of a cancer patient, a patient-characteristic time course of expression of one or several MDR-associated genes can be observed in his tumor cells. It appears that, after cytokine treatment a “therapeutic window” can be determined, which is patient-specific and which can be exploited to advantage for the subsequent cytostatic treatment. This is particularly of importance if the tumor tissue of the patient is removed and a cytostatic treatment will be performed for prevention of progression. It has been surprisingly shown, that also in these cases one can refer to that “therapeutic window” for the subsequent treatment with one or several MDR-associated cytotoxic substances, which has been determined before removal of the tumor.
It has been shown, that particularly gastrointestinal tumors, melanomas,, sarcomas, mammary carcinomas and glioblastomas can be treated with the procedure of the invention.
Under “cytotoxic substance” a substance is meant which is used as medicament for the treatment of malignant diseases and which acts on the basis of cytotoxicity mainly towards tumor cells. Such cytotoxic substances, which belong to the spectrum of multidrug resistance include for example daunorubicin, doxorubicin, mitoxantrone, et oposid, tenoposid, vinblastine, vincristine, actinomycin D, mitomycin C, taxol (paclitaxel), topotecan, colchicine, emetin, ethidiumbromide, puromycin, gramicidin D, valinomycin and mithramycin. Such substances and their mode of action are described e.g. by U. A. German et al. in European Journal of Cancer 32A (1996):927-944. Cis-platinum can likewise be suitable cytotoxic substances.
Under “cytokine” a substance is meant, which posses as cellular, physiological messenger immunstimulatory or also cytostatic properties and which can be used for cytotoxic or cytostatic tumor therapy. Suitable cytokines include for example interleukins such as IL-2, interferons, such as IFN&agr; and IFNy and tumor necrosis factors such as TNF&agr; etc.
Under “multidrug resistance-associated gene” (MDR-associated gene) a gene is meant, which codes for a protein causally involved in the development of the multidrug resistance phenotype, such as e.g. the energy-dependent transmembrane drug efflux pump (mdr1, U. A. German et al. Eur. J. Cancer 32A (1996):927-944; Mrp, D. W. Loe et al. Eur. J. Cancer 32A (1996):945-957) or which causes the nucleo-cytoplasmatic transport of a drug (e.g. Lrp, Izquierdo et al. Eur. J. Cancer 32A
Schlag Peter
Stein Ulrike
Walther Wolfgang
Goodwin & Procter LLP
Lankford , Jr. Leon B.
Max-Delbrück-Centrum für Molekulare Medizin
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