Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Reexamination Certificate
2000-12-12
2003-04-15
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
C514S476000, C514S478000, C514S483000, C514S491000, C514S499000, C514S922000, C514S825000, C514S826000
Reexamination Certificate
active
06548540
ABSTRACT:
FIELD OF INVENTION
This invention generally relates to methods of treating cancer, and particularly to methods of treating cancer using dithiocarbamate derivatives.
BACKGROUND OF THE INVENTION
Cancer, the uncontrolled growth of malignant cells, is a major health problem of the modem medical era and ranks second only to heart disease as a cause of death in the United States. While some malignancies, such as adenocarcinoma of the breast and lymphomas such as Hodgkin's Disease, respond relatively well to current chemotherapeutic antineoplastic drug regimens, other cancers are poorly responsive to chemotherapy, especially non-small cell lung cancer and pancreatic, prostate and colon cancers. Even small cell cancer of the lung, initially chemotherapy sensitive, tends to return after remission, with widespread metastatic spread leading to death of the patient. Thus, better treatment approaches are needed for this illness. Also, because almost all currently available antineoplastic agents have significant toxicities, such as bone marrow suppression, renal dysfunction, stomatitis, enteritis and hair loss.
The end of the twentieth century has seen a more dramatic increase in the observed incidence of malignant melanoma than for all other types of tumors. The biology of malignant melanomas offers an example of the importance of transcription factors for malignant cell propagation. Malignant melanomas have great propensity to metastasize and are notoriously resistant to conventional cancer treatments such as chemotherapy and &ggr;-irradiation. Development of malignant melanoma in humans progresses through a multistage process, with transition from melanocyte to nevi, to radial growth, and subsequently to the vertical growth, metastatic phenotype of autonomous melanomas, associated with decreased dependence on growth factors, diminished anchorage dependence, reduced contact inhibition and increased radiation and drug resistance.
Much of the molecular understanding of melanoma progression has come from studying the response of cultured melanoma cells to mitogenic stimuli. In culture, melanocyte proliferation and differentiation are positively regulated by agents that increase cAMP (See, P. M. Cox, et al., “An ATF/CREB binding motif is required for aberrant constitutive expression of the MHC class II Dr&agr; promoter and activation by SV40 T-antigen,”
Nucleic Acids Res.
20:4881-4887 (1992); R. Halaban, et al., “Regulation of tyrosinase in human melanocytes grown in culture,”
J. Cell Biol.
97:480-488 (1983); D. Jean, et al., “CREB and its associated proteins act as survival factors for human melanoma cells,”
J. Biol. Chem.
273:24884-24890 (1998); P. Klatt, et al., “Nitric oxide inhibits c-Jun DNA binding by specifically targeted S-glutathionylation,”
J. Biol. Chem.
274:15857-15864 (1999); J. M. Lehmann, et. al., “MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily,”
Proc. Natl. Acad. Sci. U.S.A.
89:9891-9895 (1989); M. Luca, et al., “Direct correlation between MUC18 expression and metastatic potential of human melanoma cells,”
Melanoma Res.
3:35-41(1993); J. P. Richards, et al., “Analysis of the structural properties of cAMP-responsive element-binding protein (CREB) and phosphorylated CREB,”
J. Biol. Chem.
271:13716-13723 (1996); and S. Xie, et al., “Dominant-negative CREB inhibits tumor growth and metastasis of human melanoma cells,”
Oncogene
15:2069-2075 (1997)), and several cAMP responsive transcription factors binding to CRE (the consensus motif 5′-TGACGTCA-3′, or cAMP response element) play prominent roles in mediating melanoma growth and metastasis. In MeWo melanoma cells, the transcription factor CREB (for CRE-binding protein) and its associated family member ATF-1 promote tumor growth, metastases and survival through CRE-dependent gene expression. See, D. Jean, et al., supra. Expression of the dominant negative KCREB construct in metastatic MeWo melanoma cells decreases their tumorigenicity and metastatic potential in nude mice. See, S. Xie, et al., “Expression of MCA/MUC18 by human melanoma cells leads to increased tumor growth and metastasis,”
Cancer Res.
57:2295-2303 (1997). The KCREB-transfected cells display a significant decrease in matrix metalloproteinase 2 (MPP2, the 72 kDa collagenase type IV) mRNA and activity, resulting in decreased invasiveness through the basement membrane, an important component of metastatic potential.
The cell surface adhesion molecule MCAM/MUC18, which is involved in metastasis of melanoma (See, J. M. Lehmann, et al., supra; M. Luca, et al., supra; S. Xie, et al., supra), is also down-regulated by KCREB transfection. See, S. Xie, et al.,
Cancer Res.
, supra. In addition, expression of KCREB in MeWo cells renders them susceptible to thapsigargin-induced apoptosis, suggesting that CREB and its associated proteins act as survival factors for human melanoma cells, thereby contributing to the acquisition of the malignant phenotype. See, D. Jean, et al., supra.
Melanoma cells aberrantly express the major histocompatibility complex class II (MHC II) antigens, normally found only in B-lymphocytes and antigen presenting cells of the monocyte/macrophage cell line. See, P. M. Cox, et al., “An ATF/CREB binding motif is required for aberrant constitutive expression of the MHC class II Dr&agr; promoter and activation by SV40 T-antigen.
Nucleic Acids Res.,”
20:4881-4887 (1992). In B
16
melanoma cells this is due to activation of the MHC II DR&agr; promoter by constitutive activation of an ATF/CREB motif. CREB family proteins also bind to the UV-response element (URE, 5′-TGACAACA-3′), and URE binding of the CREB family member ATF2 confers resistance to irradiation and to the chemotherapeutic drugs cis-platinum, 1&bgr;-D-arabinofuranosylcytosine (araC) or mitomycin C in MeWo melanoma lines. See, Z. Ronai, et al., “ATF2 confers radiation resistance to human melanoma cells,”
Oncogene
16:523-531 (1998)). Thus, CREB family transcription factors play important roles in the malignant potential of this important tumor type. This has led to the suggestion by others that targeted molecular disruption of ATF/CREB-mediated transcription might be therapeutically useful for controlling growth and metastases of relatively treatment-resistant malignant melanoma. See, D. Jean, supra, and Z. Ronai, supra.
The positively charged DNA binding domain of many transcription factors contains cysteines which can be oxidatively modified by agents such as hydrogen peroxide or nitric oxide (NO), stimulating repair processes that result in formation of mixed disulfides between glutathione (GSH) and protein thiols. See, P. Klatt, et al., supra; and H. Sies, “Glutathione and its role in cellular functions,”
Free Rad. Biol. Med.
27:916-921 (1999)). As a consequence of this so-called protein “S-glutathionylation”, the usually positively charged transcription factor DNA binding domain develops an electronegative charge imparted by dual carboxylate end groups of GSH. The change in charge disrupts transcription factor binding to its respective DNA consensus sequence. See, P. Klatt, et al., supra and H. Sies, supra. This mechanism has been demonstrated to explain how NO inhibits c-Jun DNA binding by specifically targeted S-glutathionylation of cysteines within the DNA binding region, and a similar mechanism has been suggested for how nitrosative stress in general might functionally inhibit the activity of Fos, ATF/CREB, Myb and Rel/NF&kgr;B family transcription factors. See, P. Klatt, et al., supra.
The dithiocarbamates comprise a broad class of molecules giving them the ability to complex metals and react with sulfhydryl groups and glutathione. After metal-catalyzed conversion to their corresponding disulfides, dithiocarbamates inhibit cysteine proteases by forming mixed disulfides with critical protein thiols. See, C. S. I. Nobel, et al., “Mechanism of dithiocarbamate inhibition of apoptosis: thiol oxidation by dithiocarbamate disulfides directl
Alston & Bird LLP
Charlotte-Mecklenburg Hospital Authority
Krass Frederick
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