MX2007012093A - Unit dosage forms of temozolomide - Google Patents

Abstract

This invention relates to unit dosage forms of temozolomide. These unit dosage forms are particularly well-suited for decreasing the pill burden and increasing patient compliance. The invention also relates to methods of treating proliferative disorders in a patient with these unit dosage forms. The invention additionally relates to kits comprising these unit dosage forms.

Description

FORMS OF UNITARY DOSING OF TEMOZOLOMIDE FIELD OF THE INVENTION This invention relates to unit dosage forms of temozolomide. These unit dosage forms are particularly suitable for decreasing the amount of pills and for increasing patient compliance. The invention also relates to methods for treating proliferative disorders in a patient with these unit dosage forms. The invention also relates to equipment comprising these unit dosage forms.

BACKGROUND OF THE INVENTION Brain tumors comprise approximately 2% of all malignancies. Stupp et al. , J. Clin. One, 20 (5): 1375-1 382 (2002). Each year, more than 1,700 cases are diagnosed in the United States, with approximately 13,000 associated deaths. The standard protocol for treating a malignant glioma involves cytoreduction through surgical resection, when possible, followed by radiotherapy (RT) with or without adjuvant chemotherapy. Stupp et al., Supra. A chemotherapeutic agent approved to treat brain tumors is temozolomide (Schering Corp. under the trade name Temodar® in the United States and Temodal® in Europe). Name Chemical for temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo [5,1-d] -as-tetrazin-8-carboxamide (see US Patent No. 5,260,291). It is believed that the cytotoxicity of temozolomide or its metabolite, MTIC (3-methyl- (triazen-1-yl) imidazole-4-carboxamide), is mainly due to the alkylation of DNA. The alkylation (methylation) takes place mainly at positions O6 and N7 of guanine. Temodar® capsules are currently indicated in the United States for the treatment of adult patients with recently diagnosed glioblastoma multiforme as well as with refractory anaplastic astrocytoma, ie, patients with a first relapse who have experienced the progression of the disease in a regimen. of drugs containing a nitrosourea and procarbazine. Temodal® is currently approved in Europe for the treatment of patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma for recently diagnosed patients as well as for those who have recurrence or progression after standard therapy. A typical regimen for patients with glioma who are taking temolozomide consists of two phases, a concomitant phase, followed by a maintenance phase. In the concomitant phase, the patient receives an oral administration of temozolomide at 75 mg / m2 (approximately 140 mg for a patient who has a Body Surface Area (ASC) between 1.8 and 1.9 m2) for 42 days concomitant with RT See table 1. Four weeks after completing the concomitant phase, The patient receives 6 cycles of maintenance treatment. In the first maintenance cycle, temozolomide is administered at 150 mg / m2 (approximately 280 mg for a patient who has an ASC between 1.8 and 1.9 cm) once a day for five days in a row for 23 days without treatment . The dosage can be increased up to 200 mg / m2 (approximately 360 mg for a patient possessing an ASC between 1.8 and 1.09 m2) during the first 5 days of each subsequent cycle. Currently, the capsule formulations of temozolomide contain 5, 20, 100 or 250 mg of temozolomide. If a therapeutic dose of 150 mg / mg2 is administered, a patient who possesses an ASC of between 1.8 and 1.9 would need to consume 4 capsules per day to receive the dosage of approximately 280 mg of temozolomide (1 x 250 mg, 1 x 20 mg and 2 x 5 mg). See table 2. Said high amount of pills would probably result in poor compliance of the patient with therapies that require the self-administration of temozolomide, thus producing a sub-optimal therapeutic benefit of the drug. Other factors that may affect the patient's compliance with the self-administration of the appropriate amount of pills consists of the intensity of the treatment regimens for the gliomas., which include neurosurgery and RT. Moreover, the amount of different medications that the patient may have to take to alleviate the side effects of surgery or RT or to remedy or alleviate other unrelated conditions further exacerbates the already high amount of pills. In addition, the patient is at risk of cognitive deficits and of a neurological state compromised as a result of the intense treatment regimens.

In this way, there is a need to improve the way unit dosage of temozolomide. Said improved dosage form it would reduce the amount of pills and increase patient compliance.

TABLE 1 * 100 mg / rn daily represents the current minimum dosage for patients in maintenance dosing TABLE 2 BRIEF DESCRIPTION OF THE INVENTION The present invention provides an improved unit dosage form of temozolomide comprising about 140 mg of temozolomide. The present invention also provides an improved unit dosage form of temozolomide comprising about 180 mg of temozolomide. These unit dosage forms reduce the amount of pills and increase patient compliance. In some embodiments, the unit dosage forms are in the form of a capsule. In some embodiments, the capsules are color-coded. In some embodiments, the 140 mg temozolomide capsule differs in color from the 180 mg temozolomide capsule. The present invention also provides methods for increasing patient compliance with a regimen by administering these unit dosage forms. The present invention also provides methods for treating proliferative disorders with these unit dosage forms. In some embodiments, the proliferative disorder is selected from a glioma, melanoma, lung cancer, lymphoma, cancer of the head and neck, ovarian cancer, colorectal and / or colon cancer or cancer of the esophagus, or other malignancy hematologic or solid tumor.

In some embodiments, methods for treating proliferative disorders comprise administration of the unit dosage forms according to a dosage regimen. In some embodiments, the regimen is based on the methylation status of the promoter region of the 06-methylguanine-DNA transferase (MGMT) gene in a sample obtained from the patient. In other embodiments, the regimen is based on the presence or absence of the MGMT protein in a sample obtained from the patient. In other embodiments, the regimen is based on the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient. In other embodiments, the regimen is based on the presence (or level) of MGMT messenger RNA in a sample obtained from the patient. The present invention also provides equipment comprising these unit dosage forms. In some embodiments, the equipment comprises both unit dosage forms. In some embodiments, the kits further comprise one or more unit dosage forms comprising approximately 5, 20 or 100 mg of temozolomide. In some modalities, the equipment consists of a blister pack.

DETAILED DESCRIPTION OF THE INVENTION In order that the invention described herein can be fully understood, the following detailed description is set forth. Unless defined otherwise, all terms Technicians and scientists used herein have the same meaning as those commonly understood by one skilled in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods and examples are illustrative only, and are not intended to be limiting. All publications, patents and other documents mentioned herein are incorporated by reference in their entirety. In order to further define the invention, the following terms and definitions are provided herein. The term "pharmaceutically acceptable carrier or adjuvant" refers to a non-toxic carrier or adjuvant that can be administered to a patient, together with temolozimide, and that does not destroy the pharmacological activity of it. The term "color-coded capsule" refers to a capsule in which any portion or the entire capsule is colored and the color represents a particular meaning, for example a given capsule color represents a specific dosage amount of temozolomide. The term "treat" or "treatment" is intended to denote the alleviation or alleviation of the symptoms of a cell proliferative disorder in a mammal such as a human or in the improvement of a testable measurement associated with a cell proliferative disorder. The term "patient" refers to an animal that includes a mammal (e.g., a human). The term "proliferative disorder" may consist of a neoplasm. These neoplasms are either benign or malignant. The term "neoplasm" refers to a new, abnormal cell growth or abnormal cell growth that reproduces faster than normal. A neoplasm creates an unstructured mass (a tumor) which can be either benign or malignant. The term "benign" refers to a tumor that is non-cancerous, for example, its cells do not invade the surrounding tissues or do not metastasize to distant sites. The term "malignant" refers to a tumor that is cancerous, metastatic, that invades contiguous tissue or that is no longer under normal cell growth control. The term "brain tumor" includes glioma, glioblastoma multiforme, ependymoma; astrocytoma, medulloblastoma, neuroglioma, oligodendroglioma and meningioma. The term "sample" refers to a specimen that can be obtained or isolated from normal or tumoral tissue, brain tissue, cerebrospinal fluid, blood, plasma, serum, urine, excrement, saliva, lymph, lymph nodes, spleen, liver, marrow bone, or any other biological specimen that contains either MG T protein or nucleic acid of the gene MGMT. The term "MGMT" refers to O6-methylguanine-DNA methyltransferase. MGMT is also known as a 06-alkylguanine-DNA-alkyltransferase (AGAT). The term "GM-CSF" denotes a protein that (a) possesses an amino acid sequence that is substantially identical to the mature human GM-CSF sequence (ie, lacking a signal peptide) described by Lee et al. , Proc. Nati Acad. Sci. United States, 82: 4360 (1985) and that (b) possesses a biological activity that is common to native GM-CSF. The term "substantial identity of amino acid sequences" means that the sequences are identical or differ in one or more alterations of amino acids (deletions, additions, substitutions) that do not substantially affect biological activity. The term "equipment" refers to one or more containers for containing the unit dosage forms of the present invention.

Unit dosage forms The present invention provides a unit dosage form of temozolomide comprising about 140 mg of temozolomide and a pharmaceutically acceptable carrier. The present invention also provides a unit dosage form of temozolomide comprising about 180 mg of temozolomide and a pharmaceutically acceptable carrier. In some embodiments, the unit dosage form is suitable for oral administration. Pharmaceutically acceptable carriers that can be used in the dosage forms of the present invention include those well known in the art (see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mac Publishing Company (1980)). Said pharmaceutically acceptable carriers may include other agents, carriers, genetic carriers, adjuvants, excipients, inert diluents, medicinal lubricating agents, etc., such as plasma or human serum albumin preparations. Nonaqueous vehicles such as fixed oils and ethyl oleate are also useful herein. Examples of diluents include calcium carbonate, potato starch, alginic acid, and lactose. Examples of inert diluents include lubricating agents, such as magnesium stearate. Preferably, the pharmaceutically acceptable carriers are anhydrous lactate, colloidal silicon dioxide, sodium starch glycolate, tartaric acid and stearic acid. The unit dosage forms according to the present invention may be prepared in the form of tablets, pills, granules, dispersible powders or capsules. Preferably, the unit dosage forms are in the form of capsules. In some embodiments, the capsules are color-coded for easy identification. In some embodiments, the 140 mg temozolomide capsule differs in color from the 180 mg temozolomide capsule. In some embodiments, the potency of each capsule has a different color, thus indicating the dosage of the young man measure it.

Methods for increasing patient compliance The unit dosage forms of the present invention can be used to increase patient compliance by reducing the amount of pills. In some embodiments, the present invention provides methods of increasing patient compliance by administering to the patient one or more unit dosage forms containing approximately 140 mg or 180 mg of temozolomide. In some embodiments, the methods further comprise administering one or more unit dosage forms containing about 5 mg, 20 mg or 100 mg of temozolomide. The unit dosage forms can be administered to a patient according to a dosing regimen and / or a dosing scheme. Non-limiting examples of regimens and dosing schemes are illustrated in Table 3.

TABLE 3 Intensity of the dose dose levels of TMZ * Represents the total dose received in a 3-week cycle The dosing regimes of Table 3 can be simplified by using the unit dosage forms of the present invention. The suggested capsule combinations using the unit dosage forms of the present invention are illustrated in Table 4. In 18 of 29 daily doses listed in Table 4, the suggested capsule combinations of the present invention are less than combinations in capsules currently available. See Table 5. Notably, the suggested capsule combinations of the present invention are increased by only 2 daily doses (see, 255 mg and 370 mg in Table 2 compared to Table 4). By simplifying dosing regimens, the amount of pills for the patient is significantly reduced. In particular, a patient with a regimen of 195 mg temozolomide per day would need to consume 8 of the formulations in current capsules to achieve therapeutic dosing (ie, 1 x 1000 mg, 4 x 20 mg and 3 x 5 mg). See Tables 2 and 5. However, using the unit dosage forms of the present invention, that patient would need to consume only 4 unit dosage forms (ie, 1 x 180 mg and 3 x 5 mg). See Tables 4 and 5. As another example, a patient with a regimen of 280 mg temozolomide per day would need to consume 4 of the formulations in current capsules to achieve therapeutic dosing (ie, 1 x 250 mg, 1 x 20 mg and 2 x 5 mg). See tables 2 and 5. However, using the unit dosage forms of the present invention, that patient would need to consume only 2 unit dosage forms (i.e., 2 x 140 mg). See Tables 4 and 5. Still as another example, a patient with a regimen of 380 mg temozolomide per day would need to consume 5 of the formulations in current capsules to achieve therapeutic dosing (ie 1 x 250 mg, 1 x 100 mg, 1 x 20 mg and 2 x 5 mg). See Tables 2 and 5. Conversely, that patient would need to consume only 3 unit dosage forms of the present invention (ie, 2 x 180 mg and 1 x 20 mg). See Tables 4 and 5. Table 6 further illustrates how the unit dosage forms of the present invention decrease the amount of pills for the patient. As shown in Table 6, the number of capsules is lower in 28 of 45 regimens when the patient receives the unit dosage forms of the present invention. See Table 6. Notably, the amount increases in only 8 of the remaining 1 7 regimes.

TABLE 4 Combinations in Suggested Capsules Based on the Daily Dose in Adults Number of Daily Capsules in Power * Assume rounding TABLE 5 TABLE 6 Methods of treatment of proliferative disorders The unit dosage forms of the present invention can be used to treat a proliferative disorder in a patient. Proliferative disorders include, but not limited to, benign / malignant tumors such as brain tumors, prostate cancer, lung cancer, breast cancer, ovarian cancer, testicular cancer, liver, kidney, spleen, bladder, colorectal and / or colon cancer, of head and neck, melanoma, carcinoma, sarcoma, lymphoma, mycosis fungoides as well as leukemia or other hematological malignancies. In some modalities, the methods are used to treat glioma, melanoma, lung cancer, lymphoma, colorectal and / or colon cancer, head and neck or ovarian cancer. In some modalities, the methods are used to treat glioma. In some embodiments, the unit dosage forms of the present invention are administered according to one of the dosing regimens presented in tables 3 and 4. In some embodiments, the dosage regimen is 150-200 mg / m2 per day for 5 days in a 28-day cycle. In other embodiments, the dosage regimen is 100 mg / m2 per day for 14 days in a 21-day cycle. In other embodiments, the dosage regimen is 150 mg / m2 per day for 7 days in a 14-day cycle. In some embodiments, the unit dosage forms of the present invention are used to treat glioma. In some embodiments, the unit dosage forms are administered to a patient who possesses a glioma according to one of the dosing regimens presented in tables 3 and 4. In some embodiments, the dosage regimen is 1 50-200 mg / m2 per day for 5 days in a 28-day cycle. In other embodiments, the dosage regimen is 100 mg / m2 per day for 14 days in a 21-day cycle. In other preferred embodiments, the dosage regimen is 1 50 mg / m2 per day for 7 days in a 14 day cycle. In some embodiments, the unit dosage forms are administered in combination with a growth factor. Suitable growth factors include, but are not limited to, GM-CSF, G-CSF, IL-1. IL-3, IL-6, or erythropoietin. Non-limiting growth factors include Epogen® (epoetin alfa), Procrit®. (epoetin alfa), Neupogen® (filgrastim, a human G-CSF), Aranesp® (hyperglycosylated recombinant alpha darbepoetin), Neulasta® (also known brand Neupopeg, pegylated recombinant filgrastim, pegfilgrastim), Albupoietin ™ (a long-acting erythropoietin ), and Albugranin ™ (G-CSF albumin, a long-acting G-CSF). In some embodiments, the growth factor is G-CSF. In some embodiments, the unit dosage forms are administered in combination therapy. In some embodiments, the unit dosage forms are administered in combination with an inhibitor of poly (ADP-ribose) polymerase (s) (PARP). The PARP inhibitor can be administered either before, concomitantly with or after administration of the unit dosage forms of the present invention. Suitable PARP inhibitors include but are not limited to CEP-6800 (Cephalon, described in Miknyoczki et al., Mol Cancer, Ther, 2 (4): 371-382 (2003)); 3-aminobenzamide (also known as 3-AB; Inotek; described in Liaudet et al., Br J Pharmacol, 33 (8): 1424-1430 (2001)); PJ34 (Inotek, described in Abdelkarim et al., Int J Mol Med, 7 (3): 255-260 (2001)); 5-iodo-6-amino-1,2-benzopyrone (also known as INH (2) BP; Inotek; described in Mabley et al., Br J Pharmacol, 133 (6): 909-919 (2001), GPI 1 5427 (described in Tentori et al., Int J Oncol, 26 (2): 41 5-422 (2005)); 1,5-dihydroxyisoquinoline (also known as DIQ; described in Walisser and Thies, Exp Cell Res, 251 ( 2): 401 -41 3 (1,999); 5-aminoisoquinolinone (also known as 5-AIQ; described in Di Paola et al., Eur J Pharmacol, 492 (2-3): 203-210 (2004); AG14361 (described in Bryant and Helleday, Biochem Soc Trans, 32 (Pt 6): 959-961 (2004), Veuger et al., Cancer Res, 63 (18): 6008-6Ü1 5 (2003), and Veuger et al. , Oncogene, 23 (44): 7322-7329 (2004)), ABT-472 (Abbott), INO-100 (Inotek), AAI-028 (Novartis), KU-59436 (KuDOS, described in Farmer et al., "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy," Nature, 434 (7035): 91 7-921 (2005)), and those described in Jagtap et al., Crit Care Med, 30 (5): 1071-1082 (2002); Loh et al., Bioorg Med Chem L ett, 1 5 (9): 2235-2238 (2005); Ferraris et al. , J Med Chem, 46 (14): 3138-31 51 (2003); Ferraris et al. , Bioorg Med Chem Lett, 1 3 (1 5): 2513-2518 (2003); Ferraris et al. , Bioorg Med Chem, 11 (17): 3695-3707 (2003); Li and Zhang IDrugs, 4 (7): 804-812 (2001); Steinhagen et al. , Bioorg Med Chem Lett, 2 (21): 3 87-3190 (2002)); WO 02/06284 (Novartis); WO 02/06247 (Bayer); PARP inhibitors under development by MGI Pharma Inc. (previously Guildford Pharmaceutical, Inc.) which include PARP inhibitors described in W099 / 1 1645 (incorporated herein by reference in its entirety) which include PARP inhibitors termed "1,1,1-dihydro (1) benzopyran (4.32). -de) isoquinolin-3 (2H) -one "such as GPI 1 5427 designated" 10- (4-methyl-piperazin) -1-methylmethyl) -2H-7-oxa-1,2-diazabenzo [de] anthracene-3 -one "; GPI 16539 designated "2- (4-methyl-piperazin-1-yl) -5H-benzo [c] [1,5] naphthyridin-6-one"; GPI21016, GPI 16346 and GPI 18180, GPI 6150, GPI 18078; GPI 6000 as well as 2-phenyl benzimidazole 4-carboxamides including those described by Agouron / Pfizer in WO / 09524379 include OD as for example in 16th NCI-EROTC Symposium New Drugs Cancer Therapy (Amsterdam) 1998 Abs 1 6; Agouron 91 st AACR (San Francisco) 2000, Abs. 5164 including AG-014699, AG-14361, AG-14073, as well as Kudos's KU59436, KU-0687, etc. In some embodiments, the unit dosage forms are administered in combination with an 06-alkylguanine-DNA-alkyltransferase (Atase) inhibitor such as 06-benzylguanine (O6BG) or Lomeguatrib [6- (4-bromo-2-thienyl) methoxy) ] purin-2-amine] (also known as Patrin ™ or Patrin-2) described in U.S. Patent No. 6,043,228 (Cancer Research UK) for accentuating hematopoietic toxicity. The Atasa inhibitor such as 06BG can be administered either before, concomitantly with or after administration of the unit dosage forms of the present invention. In some embodiments, the unit dosage forms are administered in combination with an antiemetic agent. Suitable antiemetic agents include, but are not limited to, Palonosetron, Tropisetron, Ondansetron, Granisetron, Bemesetron or a combination of at least two of the foregoing. In some embodiments, the amount of active antiemetic substance in a dosage unit is 2 to 10 mg, with an amount of 5 to 8 mg of active substance in a dosage unit being especially preferred. A daily dosage generally comprises an amount of active substance of 2 to 20 mg, an amount of active substance of 5 to 16 mg is particularly preferred. In some embodiments, a neurokinin-1 antagonist (NK-1 antagonist) such as aprepitant can be administered either alone or in combination with a steroid such as dexamethasone in conjunction with an antiemetic agent. In other embodiments, the unit dosage forms are administered in combination with an NK-1 agonist alone or with a steroid. In certain embodiments, the NK-1 antagonist is one or more of the NK-1 antagonists described in U.S. Patent No. 7,049,320 alone or in combination with one or more of a 5HT3 inhibitor and a steroid. In some embodiments, the unit dosage forms are administered in combination with a farnesyl protein transferase inhibitor. In other embodiments, the unit dosage forms are administered with another antineoplastic agent. Antineoplastic agents Suitable include, but are not limited to, Uracil Mustard, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6 -Mercaptopurine, 6-Thioguanine, Fludarabine Phosphate, Pentostatin, Gemcitabine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Paclitaxel, Mithramycin, Deoxicoformycin, Mitomycin-C, L-Asparaginase, Interferons, Etoposide , Teniposide 7a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone Propionate, Testolactone, Megestrol Acetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone Acetate, Leuprolide, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafina, Droloxafina, Hexamethylmelamine, Oxaliplatin (Eloxatin®), Iressa (gefinitib, Zd1839), XELODA® (capecitabine), Tarceva® ( erlotinib), Azacitidine (5-Azacytidine; 5-AzaC), and mixtures thereof. In some embodiments, the unit dosage forms can be administered with other anti-cancer agents such as those disclosed in U.S. Patent Nos. 5,824,346, 5,939,098, 5,942,247, 6,096,757, 6,251, 886, 6,316,462, 6,333,333, 6,346,524, Y 6,703,400, all of which are incorporated by reference.

Methods to assess the methylation status of the MGMT gene Temozolomide, as an alkylating agent, causes cell death by binding to DNA which structurally distorts the helical structure of DNA by preventing transcription and translation of DNA. In normal cells, the damaging action of the alkylating agents can be repaired through cellular DNA repair enzymes, in particular MGMT. The level of MGMT varies in tumor cells, even among tumors of the same type. The gene encoding MGMT is not commonly mutated or deleted. Rather, the low levels of MGMT in tumor cells are due to an epigenetic modification; the promoter region of MGMT is methylated, thereby inhibiting the transcription of the MGMT gene and preventing the expression of MGMT. The United States Publication 20060100188, the entire contents of which are incorporated by reference, discloses methods for treating cancer in a patient that comprise the administration of temozolomide in accordance with a regimen and / or improved dosage schedules based on the patient's MGMT level. In some embodiments, the dosage regimen is based on the methylation status of the MGMT gene in a sample obtained from the patient. In some embodiments, the methylation status is evaluated by a determination of whether the MGMT gene is methylated. In other modalities, the Methylation status is assessed by a quantitative determination of the level of methylation of the MGMT gene. In other embodiments, the state of methylation is evaluated by determining whether the MGMT protein is expressed. Even in other embodiments, the methylation status is evaluated by a determination of the level of MGMT protein expressed or the measurement of the enzymatic activity of MGMT in the patient sample. The evaluation of whether the MGMT gene is methylated can be carried out using any method known to one skilled in the art. Useful techniques for detecting the methylation of a gene or nucleic acid include, but are not limited to, those described by Ahrendt et al., J. Nati. Cancer Inst., 91: 332-339 (1999); Belsinky et al., Proc. Nati Acad. Sci. United States, 95: 1 1891-1 1896 (1998), Clark et al., Nucleic Acids Res., 22: 2990-2997 (1994); Herman et al., Proc Nati Acad Sci United States, 93: 9821-9826 (1996); Xiong and Laird, Nucleic Acids Res., 25: 2532-2534 (1997); Eads et al. , Nuc. Acids Res., 28: e32 (2002); Cottrell et al., Nucleic Acids Res., 32: 1-8 (2004). The methylation-specific PCR (MSP) can quickly assess the methylation status of virtually any group of CpG sites within a CpG island, regardless of the use of restriction enzymes sensitive to methylation. See, MSP; Hermán et al., Proc. Nati Acad Sci. United States, 93 (18): 9821-9826 (1996); Esteller et al., Cancer Res., 59: 793-797 (1999)) see also U.S. Patent No. 5,786,146, issued July 28, 1998; U.S. Patent No. 6,071,704, issued January 25, 2000; U.S. Patent No. 6,200, 756, issued March 1, 2001; and U.S. Patent No. 6,265,171, issued July 24, 2001; U.S. Patent No. 6,773,897 issued August 10, 2004; whose complete contents are incorporated herein by reference. The MSP assay involves the initial modification of DNA by sodium bisulfite, converting all unmethylated, but not methylated, cytosines to uracil, and subsequent amplification with specific primers for methylated versus non-methylated DNA. MSP requires only small amounts of DNA, is sensitive to 0.1% of methylated alleles of a given CpG island site, and can be performed on extra DNA from samples embedded in paraffin. MSP eliminates the false-positive results inherent in previous PCR-based approaches that relied on differential restriction enzymatic cleavage to distinguish methylated from non-methylated DNA. This method is very simple and can be used in small amounts of tissue or few cells. As would be understood by those skilled in the art, if the gene encoding MGMT is not methylated, the MGMT protein is expressed and can be detected (for example, by Western blot, immunohistochemical techniques or enzymatic assays for MGMT activity, etc.) as detailed below in this. An illustrative example of a Western blot assay useful for this embodiment of the invention for measuring MGMT protein level in patient samples is presented in U.S. Patent No. 5.81, 7,514 by Li et al. , whose full disclosure is incorporated in this as reference. Li et al. described monoclonal antibodies capable of specifically binding either to native human MGMT protein or to human MGMT protein having an active site which is alkylated. An illustrative example of an immunohistochemical technique useful for this embodiment of the invention for measuring the level of MGMT protein in patient samples is presented in U.S. Patent No. 5,407,804, the complete disclosure of which is incorporated herein by reference. Monoclonal antibodies are revealed which are capable of specifically binding to the MGMT protein in single cell preparations (immunohistochemical staining assays) and in cell extracts (immunoassays). The use of fluorescent reading coupled with digitization of the cell image is described and allows the quantitative measurement of MGMT levels in patient and control samples, including but not limited to tumor biopsy samples. Useful techniques to measure the enzymatic activity of protein MGMT include but are not limited to the methods described by: Mymes et al. , Carcinogenesis, 5 1061-1064 (1984); Futscher et al. , Cancer Comm. , 1: 65-73 (1989); Kreklaw et al., J. Pharmacol. Exper. Ther., 297 (2): 524-530 (2001); and Nagel et al. , Anal. Biochem. , 321 (1): 38-43 (2003), whose full disclosures are incorporated herein in their entirety. The level of MGMT protein expressed in a sample obtained from a patient can be evaluated by measuring the MGMT protein, for example, by Western blot using an antibody specific to MGMT, see example, U.S. Patent No. 5.81, 7,514. The level of MGMT expressed in a sample can also be assessed by measuring the MGMT protein using an immunohistochemical technique in a defined number of patient cells, for example, using a labeled antibody specific for MGMT and comparing the level with that expressed by the same defined number of normal Istanocytes known to express MGMT (see, for example, U.S. Patent No. 5,407,804 by Yarosh for a description of useful quantitative immunohistochemical assays). Alternatively, the level of MGMT can be evaluated by enzymatic assay, i.e. the ability to methylate the position of guanine O6 or N7 of the DNA. In each of these methods, the level of expressed MGMT protein expressed is compared to that expressed by the normal Istanocytes known to express MGMT. The MGMT protein levels of the patient are classified as follows: Low = 0-30% of the MGMT expressed by normal lymphocytes; Moderate = 31 -70% of MGMT expressed by normal lymphocytes; and High = 71 -300% or higher of the MGMT expressed by normal lymphocytes. The MGMT levels of the patient are classified as follows: Low = 0-30% of the MGMT enzyme activity of normal lymphocytes; Moderate = 31 -70% of the enzymatic activity of MGMT of normal lymphocytes; and High = 71 -300% or higher of the MGMT enzymatic activity of normal lymphocytes. The specific activity of MGMT can be evaluated and based on a comparison with known cell lines by expressing MGMT classified as follows: Low = less than 20 fmol / mg; Moderate = 20-60 fmol / mg; o High = greater than 60 fmol / mg; where the specific activity of MGMT in LOX cells is 6-9 fmol / mg, in DAOY cells it is 60-100 fmol / mg, and in A375 cells it is 80-150 fmol / mg. The methylation level of MGMT can be assessed by quantitative determination of the methylation of the gene encoding MGMT. The quantitative technique called COBRA (Xiong et al., Nuc Acids Res., 25: 2532-2534 (1997)) can be used in this determination. You can also use the "light methyl" technique of Eads et al. , Nuc. Acids Res., 28 (8): e32 (2000); U.S. Patent No. 6,331, 393. The level of methylation of the gene encoding MGMT in cells of the patient is compared to that of an equivalent number of cells of normal lymphocytes known to express MGMT. As would be understood by those skilled in the art, normal lymphocytes expressing MGMT possess a low level of methylation of the MGMT gene; conversely, cells with high methylation levels of the MGMT gene express low levels of the MGMT protein (see for example, Costello et al., J. Biol. Chem., 269 (25): 1 7228-17237 (1994)).; Qian et al., Carcinogen, 16 (6): 1385-1390 (1995)). The levels of the methylated MGMT gene of the patient are classified as follows: Low = 0-20% of the CpGs in the promoter region of the MGMT gene are methylated; Moderate = 21 -50% of the CpGs in the promoter region of the MGMT gene are methylated; and High = 51 -100% of the CpGs in the promoter region of the MGMT gene are methylated.

COBRA can also be used to quantitatively determine the levels of DNA methylation at specific gene sites in small amounts of genomic DNA. Enzymatic restriction digestion is used to reveal differences in the sequence of methylation in PCR products of DNA treated with sodium bisulfite. (Taño et al., Proc. Nati Acad. Sci. United States, 87: 686-690 (1990) describe the isolation and sequence of the human MGMT gene). The methylation levels in the original DNA sample are represented by the relative amounts of digested and undigested PCR product in a linearly quantitative fashion across a broad spectrum of DNA methylation levels. This technique can be reliably applied to DNA obtained from tissue samples embedded in microdissected paraffin. COBRA combines the powerful features of ease of use, quantitative accuracy, and compatibility with paraffin sections. An illustrative example of an RT-PCR assay useful for evaluating the MGMT mRNA level is described in Watts et al., Mol. Cell. Biol., 1 7 (9): 5612-5619 (1997). Briefly, total cellular RNA is isolated by the cell lysis of guanidium isothiocyanate followed by centrifugation through a 5.7 M CsCl gradient for 2.5 h at 205,000 xg. The RNA is quantified in a Beckman TL-100 spectrophotometer through absorbance measurements at 260 nm. Total cellular RNA is reverse transcribed by incubation of a 40 pl reaction mixture composed of 200 ng RNA; pH regulator 1 x PCR (10 mM Tris [pH 8.3], 50 mM KCI, MgCl 2 1. 5 mM); each dATP, dCTP, dGTP, and 1 mM dTTP; 200 pmol of random hexamer, 40 U of RNasin, and 24 U reverse transcriptase of the avian myeloblastosis virus (Boehringer Mannheim, Indianapolis, Ind.) At 42 ° C for 60 min. The reaction is then stopped by incubation at 99 ° C for 10 min. The specific MGMT PCR is carried out by the addition of 80 μ? of amplification reaction pH regulator (pH x PCR regulator, 25 pmol of specific MGMT primers and / or a control sequence, and 2 U of Taq DNA polymerase) at 20 μ? of the reverse transcription reaction mixture followed by incubation at 94 ° C for 5 min; 30 cycles of 94 ° C. for 1 min, 60 ° C for 15 s, and 72 ° C. for 1 min; a final extension at 72 ° C. for 5 min; and rapid cooling to 4 ° C. For example, the upstream primer sequence from exon 4 (nt 665 to 684) of the MGMT gene can be used. The nucleotide positions can be derived from the cDNA sequence (Taño et al., Proc. Nati, Acad. Sci. USA, 87: 686-690 (1990)). A control primer sequence can be employed in the same cDNA reaction (eg, primers for the histone 3.3 gene). For the analysis, 10% of the respective PCR products are separated through 3% agarose gel and visualized through ethidium bromide staining.

Methods of treating a patient with a glioma based on the methylation status of the MGMT gene The unit dosage forms of the present invention are used to treat a patient who possesses a glioma. In some embodiments, the dosage regimen is based on the detection of methylated MGMT gene in a sample. When methylation of the MGMT gene is detected in a sample obtained from a patient possessing a glioma, the dosage regimen is 1 50-200 mg / m2 per day for 5 days in a 28-day cycle. When methylation is not detected, the dosage regimen is (i) 100 mg / m2 per day for 14 days in a 21-day cycle; (ii) 150 mg / m2 per day for 7 days in a 14-day cycle; or (iii) 100 mg / m2 per day for 21 days in a 28-day cycle. In some modalities, the sample consists of a tumor biopsy sample. In some embodiments, the MGMT gene is detected using MSP. In other embodiments, the dosage regimen is based on the presence or absence of MGMT protein. In those modalities that are based on the presence or absence of MGMT protein, when the MGMT protein is not detected in a sample obtained from a patient possessing a glioma, the dosage regimen is 150-200 mg / m2 per day for 5 days. days in a 28-day cycle; when the MGMT protein is detected, the dosage regimen is selected from (i) 100 mg / m2 per day for 14 days in a 21 day cycle; 150 mg / m2 per day for 7 days in a 14-day cycle; or (iii) 100 mg / m2 per day for 21 days in a 28-day cycle. In some modalities, the sample consists of a tumor biopsy sample. In some embodiments, the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzyme assay for the MGMT protein. In still other embodiments, the dosage regimen is based on the level or activity of MGMT protein detected in a sample. When the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is low, compared to that of normal lymphocytes, the dosage regimen is (i) 150-200 mg / m2 per day for 5 days in a 28-day cycle; or (i) 250 mg / m2 per day for 5 days in a 28-day cycle in combination with a growth factor. When the level or enzymatic activity of the MGMT protein is Moderate, the dosage regimen is (i) 100 mg / m2 per day for 14 days in a 28-day cycle; (ii) 300 mg / m2 per day for 5 days in a 28 day cycle in combination with a growth factor; (iií) 75 mg / m2 per day for 21 days in a 28-day cycle; or (iv) 75 mg / m2 for 42 days in a 56-day cycle. When the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is High, the dosage regimen is selected from (i) 100 mg / m2 per day for 14 days in a 21-day cycle; (I) 1 50 mg / m2 per day for 7 days in a 14-day cycle; or (iií) 100 mg / m2 per day for 21 days in a 28-day cycle. In some modalities, the sample consists of a tumor biopsy sample.

Methods of treating a patient with certain proliferative disorders based on the methylation status of the MGMT gene In some embodiments, the unit dosage forms are used to treat patients who have a proliferative disorder selected from melanoma, lung cancer, lymphoma, cancer of head, neck cancer, ovarian cancer, colorectal cancer, colon cancer and esophageal cancer. In some embodiments, the dosage regimen is based on the detection of methylated MGMT gene in a sample. When methylation of the MGMT gene is not detected in a sample obtained from a patient, the dosage regimen is (i) 100 mg / m2 per day for 14 days in a 21-day cycle; (ii) 1 50 mg / m2 per day for 7 days in a 14-day cycle; or (iii) 100 mg / m2 per day for 21 days in a 28-day cycle. In some modalities, the sample consists of a tumor biopsy sample. In some embodiments, the MGMT gene is detected using MSP. In other embodiments, the dosage regimen is based on the detection of MGMT protein in a sample. When the MGMT protein is not detected, the dosage regimen is selected from (i) 100 mg / m2 per day for 14 days in a 21-day cycle; 150 mg / m2 per day for 7 days in a 14-day cycle; or (iii) 100 mg / m2 per day for 21 days in a 28-day cycle. In some modalities, the sample consists of a tumor biopsy sample. In some embodiments, the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for MGMT protein.

In still other embodiments, the dosage regimen is based on the level or activity of MGMT protein detected in a sample. When the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, compared to that of the normal lymphocytes, the dosage regimen is (i) 100 mg / m2 per day for 14 days in a 21-day cycle; (ii) 150 mg / m2 per day for 7 days in a 14-day cycle; or (iii) 100 mg / m2 per day for 21 days in a 28-day period. In some modalities, the sample consists of a tumor biopsy sample.

Equipment comprising the unit dosage forms of the present invention Unit dosage forms of the present invention can be included in equipment. The equipment can be in any conventional configuration or form as is known in the art which is made of a pharmaceutically acceptable material, for example a cardboard or paper box, a glass or plastic bottle or jar, a bag that can be reseal (for example, to contain a "recharge" of tablets to be placed in a different container), a metal or plastic foil, such as a blister pack with individual doses to be removed by pressure from the container or a sachet-type container or envelope which can be opened by tearing to release the unit dosage form according to a therapeutic program. In some modalities, the team consists of a blister pack In other embodiments, the equipment may include more than one package to market a unit dosage form. For example, the capsules or tablets may be contained in a bottle, which in turn is contained within a box. In some modalities, the equipment is impermeable to air. In some modalities, the equipment is made of a material resistant to light. In some embodiments, the kit comprises one or more unit dosage forms comprising about 5, 20, 100, 140, or 180 mg of temozolomide. In some modalities, the equipment consists of a blister pack. The different dosage forms can be arranged in the form of capsules, tablets or pills in rows lying next to one another in the blister pack. At the time indicated by the doctor, the patient in each case would take one capsule successively, tablet or pill of each row within a short period (in particular within 5 minutes). In some modalities, the equipment may consist of an equipment approved by the FDA. In some modalities, the equipment is accompanied with instructions for administration. The equipment may also be accompanied with a notice associated with the container in a form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmacists, said notice reflects the agency's approval of the form of the compositions or human or veterinary administration. Such notice, for example, may consist of a label approved by the Administration of Food and Drugs of E.U.A. for prescription drugs or in an insert of the approved product. The unit dosage forms can also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition. In order that this invention is more fully understood, the following example is established. This example is for the purpose of illustration only and should not be construed as limiting in any way the scope of the invention.

EXAMPLE Patients with glioma participated in a clinical trial to receive treatment with temozolomide. The drug was administered at a dosage of 75 mg / m2, 150 mg / m2 or 200 mg / m2 using only the suggested capsule combinations currently available from table 6, ie capsules of 5, 20 and 100 mg. The daily dosage was determined through the patient's ASC. The majority of patients who participated in the trial had ASC on the scale of 1.8 to 2.0 (149 of 284). In examining the data with respect to the amount of pills, the present inventors unexpectedly discovered that the addition of unit dosages of about 140 and / or 180 mg of temozolomide would be beneficial in reducing the amount of the patient's pills. See table 7. As shown in table 7, the number of pills is would decrease for patients who are receiving the unit dosage forms of the present invention in 16 of the 24 possible dosing regimens. The decreased amount of pills would be especially significant in patients who have an ASC between 1.8-2.0. For these patients, the number of pills would be decreased in 6 of the 8 possible regimens.

TABLE 7

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1 .- A unit dosage form of temozolomide, comprising approximately 140 mg of temozolomide and a pharmaceutically acceptable carrier. 2. - A unit dosage form of temozolomide, comprising approximately 180 mg of temozolomide and a pharmaceutically acceptable carrier. 3. The unit dosage form according to claim 1 or 2, further characterized in that the formulation is a capsule. 4. - The unit dosage form according to claim 3, further characterized in that the capsule is color coded. 5. The unit dosage form according to claim 4, further characterized in that the temozolomide capsule of 140 mg differs in color from the temozolomide capsule of 180 mg. 6. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful to increase patient compliance with a regimen. 7.- The use of temozolomide in the elaboration of the form of unit dosage of claim 1 or 2 or a combination thereof, useful for treating a patient who possesses a glioma. 8. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a proliferative disorder selected from at least one of the group consisting of melanoma, lung cancer, lymphoma, head cancer, neck cancer, ovarian cancer, colorectal cancer, colon cancer and esophageal cancer. 9. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a glioma, wherein the unit dosage form or combination of it is adapted to be administrable in a regimen selected from the group consisting of: (a) 1 50-200 mg / m2 per day for 5 days in a 28-day cycle; (b) 250 mg / m2 per day for 5 days in a 28-day cycle in combination with a growth factor; (c) 100 mg / m2 per day for 14 days in a 28-day cycle; (d) 300 mg / m2 per day for 5 days in a 28-day cycle in combination with a growth factor; (e) 75 mg / m2 per day for 21 days in a 28-day cycle; (f) 75 mg / m2 for 42 days in a 56-day cycle; (g) 85 mg / m2 for 21 days in a 28-day cycle; (h) 350 mg / m2 per day for 5 days in a 28-day cycle in combination with a growth factor; (i) 100 mg / m2 per day for 14 days in a 21-day cycle; (j) 400 mg / m2 per day for 5 days in a 28-day cycle in combination with a factor of increase; (k) 150 mg / m2 per day for 7 days in a 14 day cycle; (I) 100 mg / m2 per day for 21 days in a 28-day cycle; (m) 150 mg / m2 per day for 14 days in a 28-day cycle; (n) 75 mg / m2 per day daily; (o) 450 mg / m2 per day for 5 days in a 28-day cycle in combination with a growth factor; (p) 1 50 mg / m2 per day for 14 days in a 21-day cycle; (q) 100 mg / m2 per day daily; (r) 250 mg / m2 per day for 7 days in a 14-day cycle in combination with a growth factor; and (s) 300 mg / m2 per day for 7 days in a 14-day cycle in combination with a growth factor. 10. The use as claimed in claim 9, wherein the regimen is selected from the group consisting of: (a) 1 50-200 mg / m2 per day for 5 days in a 28-day cycle; (b) 100 mg / m2 per day for 14 days in a 21-day cycle; and (c) 1 50 mg / m2 per day for 7 days in a 14-day cycle. 1 1 .- The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a glioma, wherein the unit dosage form or combination it is adapted to be administrable in a regimen selected from the group consisting of: (a) when methylation of the MGMT gene is detected in a sample obtained from the patient: (i) 150-200 mg / m2 per day for 5 days in a 28-day cycle; and (b) when methylation of the MGMT gene is not detected in a sample obtained from the patient: (i) 100 mg / m2 per day for 14 days in a cycle of 21 days; (ii) 1 50 mg / m2 per day for 7 days in a 14 day cycle; or (iii) 100 mg / m2 per day for 21 days in a 28-day cycle.
2. 2. The use as claimed in claim 11, wherein the sample consists of a tumor biopsy sample.
3. 3. The use as claimed in claim 1, wherein the MGMT gene is detected using methylation-specific PCR. 14. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a glioma, wherein the unit dosage form or combination of it is adapted to be administrable in a regimen selected from the group consisting of: (a) when the MGMT protein is not detected in a sample obtained from the patient: (i) 1 50-200 mg / m2 per day for 5 days in a cycle of 28 days; and (b) when the MGMT protein is detected in a sample obtained from the patient: (i) 1 00 mg / m2 per day for 14 days in a 21 day cycle; (ii) 1 50 mg / m2 per day for 7 days in a 14-day cycle; or (ii) 100 mg / m2 per day for 21 days in a 28-day cycle. 5. The use as claimed in claim 1, wherein the sample consists of a tumor biopsy sample. 16. The use as claimed in claim 1, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 17. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a glioma, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is low, compared to that of normal lymphocytes: (i) 150-200 mg / m2 per day for 5 days in a 28-day cycle; or (ii) 250 mg / m2 per day for 5 days in a 28-day cycle in combination with a growth factor; (b) when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Moderate, as compared to that of normal lymphocytes: (i) 100 mg / m2 per day for 14 days in a 28-day cycle; (ii) 300 mg / m2 per day for 5 days in a 28-day cycle in combination with a growth factor; (iii) 75 mg / m2 per day for 21 days in a 28-day cycle; or (iv) 75 mg / m2 for 42 days in a 56-day cycle; and (c) when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is High, compared to that of normal lymphocytes: (i) 100 mg / m2 per day for 14 days in a cycle of 21 days; (ii) 150 mg / m2 per day for 7 days in a 14-day cycle; or (iii) 100 mg / m2 per day for 21 days in a 28-day cycle. 18. The use as claimed in claim 7, wherein the sample consists of a tumor biopsy sample. 19. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a melanoma, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when methylation of the MGMT gene is detected in a sample obtained from the patient. 20. Use as claimed in claim 19, wherein the sample consists of a sample of tumor biopsy. twenty-one . - Use as claimed in claim 19, wherein the MGMT gene is detected using methylation-specific PCR. 22. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a melanoma, wherein the unit dosage form or combination of it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21 day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the MGMT protein is not detected in a sample obtained from the patient. 23. - The use as claimed in claim 22, in where the sample consists of a sample of tumor biopsy. 24. - The use as claimed in claim 22, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 25. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing a melanoma, wherein the unit dosage form or combination of it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the level or the enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, in comparison with that of the normal lymphocytes. 26. - The use as claimed in claim 25, wherein the sample consists of a tumor biopsy sample. 27. The use of temozolomide in the manufacture of a patient the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having lung cancer, wherein the unit dosage form or The combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21 day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when methylation of the MGMT gene is detected in a sample obtained from the patient. 28. - The use as claimed in claim 27, wherein the sample consists of a tumor biopsy sample. 29. - The use as claimed in claim 27, wherein the MGMT gene is detected using methylation-specific PCR. 30. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing lung cancer, wherein the unit dosage form or combination it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the MGMT protein is not detected in a sample obtained from the patient. 31 - The use as claimed in claim 30, wherein the sample consists of a tumor biopsy sample. 32. The use as claimed in claim 30, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 33 - The use of temozolomide in the preparation of the form of unit dosage of claim 1 or 2 or a combination thereof, useful for treating a patient having lung cancer, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 1 50 mg / m2 per day for 7 days in a 14 day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, in comparison with that of the normal lymphocytes. 34. The use as claimed in claim 33, wherein the sample consists of a tumor biopsy sample. 35. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having a lymphoma, wherein the unit dosage form or combination of it is adapted to be administrable in a regimen selected from the group consisting of; (a) 100 mg / m2 per day for 14 days in a 21 day cycle; (b) 1 50 mg / m2 per day for 7 days in a 14 day cycle; and (c) 100 mg / m2 per day for 21 days in a day of 28 days; when methylation of the MGMT gene is detected in a sample obtained from the patient. 36. - The use as claimed in claim 35, wherein the sample consists of a tumor biopsy sample. 37. - The use as claimed in claim 35, in where the MGMT gene is detected using methylation-specific PCR. 38. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having a lymphoma, wherein the unit dosage form or combination of it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the MGMT protein is not detected in a sample obtained from the patient. 39. The use as claimed in claim 38, wherein the sample consists of a tumor biopsy sample. 40. The use as claimed in claim 38, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 41 The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having a lymphoma, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, in comparison with that of the normal lymphocytes. 42. - The use as claimed in claim 41, wherein the sample consists of a tumor biopsy sample. 43. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having head and neck cancer, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 50 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when methylation of the MGMT gene is detected in a sample obtained from the patient. 44. The use as claimed in claim 43, wherein the sample consists of a tumor biopsy sample. 45. The use as claimed in claim 43, wherein the MGMT gene is detected using methylation-specific PCR. 46. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having head and neck cancer, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group that consists of: (a) 100 mg / m2 per day for 14 days in a 21 day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the MGMT protein is not detected in a sample obtained from the patient. 47. The use as claimed in claim 46, wherein sample consists of a tumor biopsy sample. 48. The use as claimed in claim 46, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 49. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having head and neck cancer, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21 day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, in comparison with that of the normal lymphocytes. 50. The use as claimed in claim 49, wherein the sample consists of a tumor biopsy sample. 51. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing ovarian cancer, wherein the unit dosage form or combination it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the methylation of the MGMT gene is detected in a sample obtained from the patient. 52. The use as claimed in claim 51, wherein the sample consists of a sample of tumor biopsy. 53. The use as claimed in claim 51, wherein the MGMT gene is detected using methylation-specific PCR. 54. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing ovarian cancer, wherein the unit dosage form or combination it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the MGMT protein is not detected in a sample obtained from the patient. 55. - The use as claimed in claim 54, in where the sample consists of a sample of tumor biopsy. 56. The use as claimed in claim 54, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 57. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing ovarian cancer, wherein the unit dosage form or combination it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, in comparison with that of the normal lymphocytes. 58. - The use as claimed in claim 57, wherein the sample consists of a tumor biopsy sample. 59 - The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having colorectal and / or colon cancer, wherein the dosage form The unit or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 150 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when methylation of the MGMT gene is detected in a sample obtained from the patient. 60. - The use as claimed in claim 59, wherein the sample consists of a tumor biopsy sample. 61 - The use as claimed in claim 59, wherein the MGMT gene is detected using methylation-specific PCR. 62. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having colorectal and / or colon cancer, wherein the form of unit dosage or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21 day cycle; (b) 50 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the MGMT protein is not detected in a sample obtained from the patient. 63. The use as claimed in claim 62, wherein the sample consists of a tumor biopsy sample. 64. The use as claimed in claim 62, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 65. - The use of temozolomide in the preparation of the form of unit dosage of claim 1 or 2 or a combination thereof, useful for treating a patient having colorectal and / or colon cancer, wherein the unit dosage form or combination thereof is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 1 50 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, in comparison with that of the normal lymphocytes. 66. - The use as claimed in claim 65, wherein the sample consists of a tumor biopsy sample. 67. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having esophageal cancer, wherein the unit dosage form or The combination thereof is adapted to be administered in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21 day cycle; (b) 1 50 mg / m2 per day for 7 days in a 14-day cycle; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when methylation of the MGMT gene is detected in a sample obtained from the patient. 68. - The use as claimed in claim 67, wherein the sample consists of a tumor biopsy sample. 69. - The use as claimed in claim 67, wherein the MGMT gene is detected using methylation-specific PCR. 70. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient possessing esophageal cancer, wherein the unit dosage form or combination it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 50 mg / m2 per day for 7 days in a 14 day cycle; and (c) 100 mg / m2 per day for 21 days in a day of 28 days; when the MGMT protein is not detected in a sample obtained from the patient. 71 - The use as claimed in claim 70, wherein the sample consists of a tumor biopsy sample. 72. The use as claimed in claim 70, wherein the MGMT protein is detected using Western blot immunoassay, an immunohistochemical technique, or an enzymatic assay for the MGMT protein. 73. The use of temozolomide in the preparation of the unit dosage form of claim 1 or 2 or a combination thereof, useful for treating a patient having esophageal cancer, wherein the unit dosage form or combination it is adapted to be administrable in a regimen selected from the group consisting of: (a) 100 mg / m2 per day for 14 days in a 21-day cycle; (b) 1 50 mg / m2 per day for 7 days in a period of 14 days; and (c) 100 mg / m2 per day for 21 days in a 28-day cycle; when the level or enzymatic activity of the MGMT protein detected in a sample obtained from the patient is Low or Moderate, in comparison with that of the normal lymphocytes. 74.- The use as claimed in claim 73, wherein the sample consists of a tumor biopsy sample. 75. - A device comprising the unit dosage form of claim 1. 76. - The equipment according to claim 74, further characterized in that it additionally comprises the unit dosage form of claim 2. 77. - A device comprising the unit dosage form of claim 2. 78. - The equipment of according to any of claims 75-77, further characterized in that the kit further comprises one or more unit dosage forms comprising about 5, 20 or 100 mg of temozolomide. 79. - The equipment according to any of claims 75-77, further characterized in that the equipment consists of a blister pack. 80. - The equipment according to claim 78, further characterized in that the equipment consists of a blister pack. 81 - The equipment according to claim 79, further characterized in that the unit dosage form is a capsule. 82. The equipment according to claim 80, further characterized in that the unit dosage form is a capsule.