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Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasmsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, LymphokineCombined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070122379, Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 11/493,429, entitled "COMBINED TUMOR SUPPRESSOR GENE THERAPY AND CHEMOTHERAPY IN THE TREATMENT OF NEOPLASMS, filed Jul. 25, 2006, which is a continuation of U.S. patent application Ser. No. 10/824,058, filed Apr. 13, 2004, which is a divisional of U.S. patent application Ser. No. 09/311,772, filed May 13, 1999, which is a continuation of U.S. patent application Ser. No. 09/024,932, filed Feb. 17, 1998, which is a non-provisional of U.S. Appl. No. 60/038,065, filed Feb. 18, 1998, and U.S. Appl. No. 60/047,834, filed May 28, 1997, the entire disclosures of which are incorporated herein by reference for all purposes. FIELD OF THE INVENTION [0002] This invention describes novel methods of treating subjects afflicted with hyperproliferative diseases such as tumors or metastatic disease. In particular, this invention provides methods of inhibiting the hyperproliferation of cells, more specifically neoplastic cells, comprising the combined use of a tumor suppressor gene or gene product and an adjunctive anti-cancer agent BACKGROUND OF THE INVENTION [0003] Chromosome abnormalities are often associated with genetic disorders, degenerative diseases, and cancer. In particular, the deletion or multiplication of copies of whole chromosomes or chromosomal segments, and higher level amplifications of specific regions of the genome are common occurrences in cancer. See, for example Smith (1991) Breast Cancer Res. Treat., 18: Suppl. 1: 5-14; van de Viler (1991) Became. Beefiest. Acta. 1072: 33-50, Sato (1990) Cancer. Res., 50: 7184-7189. In fact, the amplification of DNA sequences containing proto-oncogenes and the deletion of DNA sequences containing tumor-suppressor genes, are each frequently characteristic of tumorigenesis. Dutrillaux (1990) Cancer Genet. Cytogenet., 49: 203-217. [0004] Mutation of the p53 gene is the most common genetic alteration in human cancers (Bartek (1991) Oncogene, 6: 1699-1703, Hollstein (1991) Science, 253: 49-53). Moreover, introduction of wild-type p53 in mammalian cancer cells lacking endogenous wild-type p53 protein suppresses the neoplastic phenotype of those cells (see, e.g., U.S. Pat. No. 5,532,220). [0005] Of the many available chemotherapeutic drugs, paclitaxel, available commercially as TAXOL.RTM. (NSC number: 125973) has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23, Horwitz (1992) Trends Pharmacol. Sci., 13: 134-146, Rowinsky (1990) J. Natl. Canc. Inst., 82: 1247-1259). Recent studies on the interaction of paclitaxel and tumor suppressor gene therapy show that reduced levels of tumor suppressor (i.e., p53) correlated with increased 02/M phase arrest, micronucleation, and p53 independent paclitaxel-induced apoptosis. In contrast, surviving cells with intact p53 progressed through mitosis and transiently accumulated in the subsequent G1 phase, coincident with increased p53 and p21.sup.cip1, waf1 protein levels (Wahl (1996) Nature Med., 2:72-79). Similarly, Hawkins (1996) Canc. Res., 56: 892-898, showed that inactivation of p53 enhanced sensitivity to certain anti-mitotic agents including paclitaxel. The authors suggested that p53 may play a role in DNA repair, thereby allowing cells to progress more readily through S phase even in the presence of drugs. These studies thus suggest that tumor suppressor gene therapy and drug therapy with antimitotic agents (especially paclitaxel therapy) act at cross purposes. SUMMARY OF THE INVENTION [0006] This invention provides methods of treating hyperproliferative mammalian cells. The invention is premised, in part, on the surprising discovery that adjunctive anti-cancer agents in combination with tumor suppressor (e.g., p53) gene therapy provide an enhanced effect in inhibiting proliferation of neoplastic or other cells having deficient tumor suppressor activity. [0007] Thus, in one embodiment, this invention provides methods of treating cancer or hyperproliferative cells by contacting the cells with a tumor suppressor protein or tumor suppressor nucleic acid and with at least one adjunctive anti-cancer agent. In some embodiments, the methods include co-administration of the tumor suppressor protein or nucleic acid and the adjunctive anti-cancer agent with at least one chemotherapeutic agent. For example, a tumor suppressor nucleic acid (e.g., a nucleic acid encoding p53) can be administered with an adjunctive anti-cancer agent (e.g., paclitaxel) and a DNA damaging agent such as cisplatin, carboplatin, navelbine (vinorelbine tartate). [0008] The cancer or hyperproliferative cells are often neoplastic cells. When the cells are present in a tumor the method inhibits tumor growth and thereby provides a method of treating a cancer. Such cancers include, but are not limited to, an ovarian cancer, pancreatic cancer, a non-small cell lung cancer, small cell lung cancer, hepatocarcinoma, melanoma, retinoblastoma, breast tumor, colorectal carcinoma, leukemia, lymphoma, brain tumor, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the reticuloendothelial tissues, Wilm's tumor, astrocytoma, glioblastoma, neuroblastoma, ovarian carcinoma, osteosarcoma, renal cancer, or head and neck cancer. [0009] A preferred adjunctive anti-cancer agent is paclitaxel or a paclitaxel derivative while a preferred tumor suppressor nucleic acid is a nucleic acid that encodes a tumor suppressor protein selected from the group consisting of p53 protein and its analogues, and a retinoblastoma (RB) protein. A particularly preferred tumor suppressor nucleic acid encodes a wild-type p53 protein and a particularly preferred retinoblastoma protein is a p110.sup.RB or a p56.sup.RB. [0010] The tumor suppressor nucleic acid is preferably delivered to the target cell by a vector. Such vectors' viruses have been modified by recombinant DNA technology to enable the expression of the tumor suppressor nucleic acid in the target cell. These vectors may be derived from vectors of non-viral (e.g., plasmids) or viral (e.g., adenovirus, adenoassociated virus, retrovirus, herpes virus, vaccinia virus) origin. In the preferred practice of the invention, the vector is a recombinantly modified adenoviral vector. Non-viral vectors are preferably complexed with agents to facilitate the entry of the DNA across the cellular membrane. Examples of such non-viral vector complexes include the formulation with polycationic agents which facilitate the condensation of the DNA and lipid-based delivery systems. An example of a lipid-based delivery system would include liposome based delivery of nucleic acids. [0011] Particularly suitable adenoviral vectors (e.g., for delivery of a nucleic acid encoding a wild-type p53 protein) comprise a partial or total deletion of a protein IX DNA. In one embodiment, the deletion of the protein IX gene sequence extends from about 3500 bp from the 5' viral termini to about 4000 bp from the 5' viral termini. The vector may also comprise a deletion of a non-essential DNA sequence in adenovirus early region 3 and/or in adenovirus early region 4 and in one embodiment the deletion is the DNA sequence E1a and/or E1b. A particularly preferred recombinant adenoviral vector for delivery of a human p53 cDNA comprises the adenovirus type 2 major late promoter or the human CMV promoter, and the adenovirus type 2 tripartite leader cDNA. One such preferred adenoviral vector is ACN53. [0012] Preferred paclitaxel or paclitaxel derivatives include paclitaxel (sold under the trademark TAXOL.RTM.) and/or TAXOTERE.RTM. (docetaxel) with paclitaxel (TAXOL.RTM.) being most preferred. Another preferred adjunctive anti-cancer is Epothilone. In one particularly preferred embodiment, the tumor suppressor is A/C/N/53 and the adjunctive anti-cancer agent is paclitaxel. [0013] The tumor suppressor protein or tumor suppressor nucleic acid can be dispersed in a pharmacologically acceptable excipient. Similarly, the adjunctive anti-cancer (e.g., paclitaxel or paclitaxel derivative) can be dispersed in a pharmacologically acceptable excipient. The tumor suppressor protein or tumor suppressor nucleic acid and said paclitaxel or paclitaxel derivative can both be dispersed in a single composition (comprising one or multiple excipient(s)). [0014] The tumor suppressor (protein or nucleic acid) and/or the adjunctive anti-cancer can be administered intra-arterially, intravenously (e.g., injected), intraperitoneally and/or intratumorally, together or sequentially. Preferred sites of administration include intra-hepatic-artery, intraperitoneal, or, where it is desired to treat cells in the head (e.g., neurological cells), into the carotid system of arteries. [0015] The tumor suppressor protein or nucleic acid can be administered in a single dose or a multiplicity of treatments, e.g., each separated by at least about 6 hours, more preferably in least three treatments separated by about 24 hours. [0016] In another preferred embodiment, the tumor suppressor protein or tumor suppressor nucleic acid is administered (with or without an adjunctive anti-cancer agent) in a total dose ranging from about 1.times.10.sup.9 to about 1.times.10.sup.14, or about 1.times.10.sup.9 to about 7.5.times.10.sup.15, preferably about 1.times.10.sup.11 to about 7.5.times.10.sup.13, adenovirus particles in a treatment regimen selected from the group consisting of: the total dose in a single dose, the total dose administered daily over 5 days, the total dose administered daily over 15 days, and the total dose administered daily over 30 days. The dose can also be administered continuously for 1 to 30 days. The paclitaxel or paclitaxel derivative is administered in a total dose ranging from 75-350 mg/m.sup.2 over 1 hour, 3 hours, 6 hours, or 24 hours in a treatment regimen selected from the group consisting of administration in a single dose, in the total dose administered daily on each of day 1 and day 2, in the total dose administered daily on each of day 1, day 2, and day 3, on a daily dosage for 15 days, on a daily dosage for 30 days, on daily continuous infusion for 15 days, on daily continuous infusion for 30 days. A preferred dose is 100-250 mg/m.sup.2 in 24 hours. Alternatively, the paclitaxel or derivative can be administered weekly at 60 mg/m.sup.2. This method of administration can be repeated for two or more cycles (more preferably for three cycles) and the two or more cycles are can be spaced apart by three or four weeks. [0017] In some preferred embodiments, a daily dose in the range of 7.5.times.10.sup.9 to about 7.5.times.10.sup.15, preferably about 1.times.10.sup.12 to about 7.5.times.10.sup.13, adenovirus particles can be administered each day for up to 30 days (e.g., a regimen of 2 days or 2 to 5 days to 14 days or 30 days with the same dose being administered each day). The multiple regimen can be repeated in recurring cycles of 21 to 28 days. Preferred routes of administration include intra-arterial (e.g., intra-hepatic artery), intratumorally, and intraperitoneally. [0018] When the tumor suppressor nucleic acid (e.g., p53) is administered in an adenoviral vector with an adjunctive anti-cancer agent (e.g., paclitaxel) and a DNA damaging agent (e.g., cisplatin, carboplatin, or navelbine), the adenoviral vector is administered for 5-14 days at about 7.5.times.10.sup.12 to about 7.5.times.10.sup.13 adenoviral particles per day. If the adenoviral vector and paclitaxel is administered with carboplatin, the dose is typically 7.5.times.10.sup.13 adenoviral particles per day. For example, a daily dose of about 7.5.times.10.sup.12 adenoviral particles can be used for administration to the lung. [0019] This invention also provides for kits for the treatment of mammalian cancer or hyperproliferative cells. The kits include a tumor suppressor protein or nucleic, acid described herein (more preferably a wild-type p53 protein or nucleic acid (e.g., in a viral or non-viral vector), or a retinoblastoma (RB) protein or nucleic acid); and an adjunctive anti-cancer agent described herein (e.g., paclitaxel or a paclitaxel derivative) and/or optionally any of the other chemotherapeutic agents described herein. The kit can optionally further include instructions describing the administration of both the tumor suppressor protein or nucleic acid and the adjunctive anti-cancer agent (and optionally an other chemotherapeutic agent) to inhibit the growth or proliferation of the cancer or hyperproliferative cells. One particularly preferred kit includes A/C/N/53 and paclitaxel. [0020] In another embodiment this invention provides pharmacological compositions comprising a tumor suppressor protein or a tumor suppressor nucleic acid and an adjunctive anti-cancer agent. In various embodiments, the pharmacological composition can optionally include any of the other chemotherapeutic compounds described herein. One particularly preferred composition includes a p53 nucleic acid (e.g., A/C/N/53) and paclitaxel. The tumor suppressor nucleic acid or protein and the chemotherapeutic agent (e.g., paclitaxel) can be in different excipients or can be contained in a single excipient as described herein. Where there are multiple excipients, the excipients can be intermixed or held separately (e.g., as in microcapsules). Continue reading about Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms... Full patent description for Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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