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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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Definitions

• the cell cycle is the series of events occurring in a cell leading to its division and duplication.
• the cycle can be divided into two periods, interphase and mitosis. Transit through these two periods of the cell cycle is known as progression or proliferation.
• interphase the cell grows, accumulates nutrients needed for mitosis and duplicates its DNA.
• mitosis the cell splits itself into two distinct daughter cells.
• Interphase includes three distinct phases, Gap 1 (Gi) phase, S phase and Gap 2 (G 2 ) phase while mitosis includes two processes.
• Gi phase includes the cell increasing in size, biosynthetic activities of the cell increasing and the synthesis of enzymes needed for DNA replication in the subsequent step.
• S phase includes the beginning of DNA synthesis and replication of all of the chromosomes.
• G 2 phase lasts until the cell enters mitosis and includes protein synthesis including the production of microtubules for mitosis.
• Mitosis includes a process where the cell's chromosomes are divided between the two daughter cells and a cytokinesis process where the original cell's cytoplasm divides forming two distinct daughter cells.
• the cell cycle also includes a resting phase, typically referred to as GQ.
• GQ resting phase
• the boundaries between the various phases for example the boundary between the Gi and S phase is referred to as a cell cycle checkpoint.
• the progression of the cell cycle can be inhibited, so that a particular cell stops the cycle at a point, a cellular checkpoint, before proceeding to the next phase.
• Cell cycle checkpoints are located between the different phases of the cell cycle, with two of the checkpoints being at the interface between the Gi and the S phase (Gi /S) and the interface between the G 2 and M phase.
• a cell cycle inhibitor can stop the progression of a cell from passing to the next phase, for example a cell can be inhibited at the Gi/S cell cycle checkpoint, which forces the cell to remain in the Gi phase until the inhibitor is removed.
• the length of the cell cycle is variable. This variability is due to differing periods spent in Gi of Go while the length of time from the beginning of S phase to the end of M phase is relatively constant.
• Conventional chemotherapeutic treatment only disrupts events in the S or M phase of the cell cycle, leaving cells in the other phases of the cell cycle relatively unharmed. For example, an alkylating agent will act in the S phase while microtubule stabilizing or disruption drugs act in the M phase.
• a particular cell is not likely to be at the S or M phase of the cell cycle at a specific time. To compensate for this, chemotherapeutic drugs must be administered repetitively, over long periods of time to increase the chances of reaching a cell which is in the specific cell cycle phase. This repetitive administration translates into larger doses of harmful drugs and an increased toxicity in a subject.
• the present invention provides a method for treating a disease or condition in a mammal which comprises the steps of; administering a therapeutically effective amount of a T type calcium channel inhibitor to effectively slow or stop progression of eukaryotic cells through the S, G 2 and M phases of the cell cycle to increase the proportion of the eukaryotic cells in the Gj phase, stopping administration of the T type calcium channel inhibitor for a period of time, and administering a dosage selected from the group consisting of a dosage of at least one chemotherapeutic agent, a dosage of radiation, and combinations thereof, to kill the proportion of eukaryotic cells progressing past the Gi phase of the cell cycle after the stopping of the administration of the T type calcium channel inhibitor.
• Figure 1 is a schematic representation of the cell cycle.
• the outer ring includes the interphase (I) and mitosis (M) stages, with the duration of mitosis in relation to the other phases being exaggerated.
• the inner ring includes the Gap 1 (Gi), Gap 2 (G 2 ) and synthesis (S) phases.
• Gap 0 (Go) or resting phase is not shown.
• Figure 2 is a graphical representation of the ability of several chemical agents to inhibit calcium influx as compared to the same chemical agent's ability to inhibit cell proliferation.
• [001 OJ Figure 3 is a schematic representation of the cell cycle and the influence several calcium channel blockers have on the progression of the cell cycle.
• Figure 4 is a graphical representation of data measured during interlaced therapy.
• Figure 5 is a graphical representation of data measured during interlaced therapy.
• treating includes administering therapy to prevent, cure, ameliorate, reduce, inhibit or alleviate/prevent the symptoms associated with, a specific disorder, disease, injury or condition.
• treating cancer includes inhibition or complete growth arrest of a tumor, reduction in the number of tumor cells, reduction in tumor size, inhibition of tumor cell infiltration into peripheral organs/tissues, inhibition of metastasis as well as relief, to some extent, of one or more symptoms associated with the disorder.
• the treatment of cancer also includes the administration of a therapeutic agent that directly decreases the pathology of tumor cells, or renders the tumor cells more susceptible to treatment by other therapeutic agents, e.g., radiation and/or chemotherapy.
• the term “treating” includes prophylaxis of the specific disorder or condition, or alleviation of the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms.
• pharmaceutically acceptable carrier, vehicle or diluent includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents. The term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.
• the term “therapeutically effective amount” means an amount of a compound of the present invention that ameliorates, attenuates, reduces or eliminates a particular disease or condition or prevents or delays the onset of a particular disease or condition.
• mammal it is meant to refer to all mammals, including, for example, primates such as humans and monkeys. Examples of other mammals included herein are rabbits, dogs, cats, cattle, goats, sheep, mice, rats and horses. Preferably, the mammal is a female or male human.
• pre-cancerous condition refers to a growth that is not malignant but is likely to become so if not treated.
• a "pre-cancerous condition” is also known as “pre-malignant condition” by one of ordinary skill in the art.
• T type calcium channel blockers are also known as "T type calcium channel inhibitors”.
• cell cycle inhibitor refers to a compound which is capable of slowing or stopping progression of a cell or cells in one stage of the cell cycle from progressing to the subsequent stage of the cell cycle.
• cytotoxin refers to a compound which is capable of causing necrosis or apoptosis to a cell which is affected by the compound.
• Varying lengths of the cell cycle are determined predominately by the time spent in the G i phase. Because of this, any particular ceil in a population will reside in Gi for a period of time before the cell enters the S phase of the cell cycle.
• a cell cycle inhibitor including a T type calcium channel inhibitor can be administered.
• the cell cycle inhibitor is first administered to a mammal in a therapeutically effective amount to effectively slow or stop progression of eukaryotic cells through the S, G 2 and M phases of the cell cycle, thereby increasing the proportion of the eukaryotic cells at the cell cycle checkpoint between the Gi and S phase (G
• the mammal may be a human. This method may be used to treat cancer and pre-cancerous conditions, and cancerous and pre-cancerous tumors in a mammal.
• the administration of the cell cycle inhibitor causes asynchronously progressing or proliferating cancer cells in a population to accumulate at Gj/S as they proceed through the cell cycle because their ability to proceed to the S phase is arrested by the cell cycle inhibitor.
• the cell For a cell to move from Gi phase to S phase through the cell cycle checkpoint, the cell requires influx of extracellular calcium to trigger biochemical cascades that are necessary for the progression. Removal of calcium from the extracellular medium blocks cell cycle transit for each cell. This blocking can be accomplished through administration of a T type calcium channel inhibitor.
• Suitable T type calcium channel inhibitors include mibefradil, elbnidipine, ethosuxamide, sutinib, TTL-1 177 (a proprietary compound, described in reference: Gray, L.
• a dosage of at least one chemotherapeutic agent, a dosage of radiation, or a dosage of both are administered, the dosage being targeted to kill cells in the S phase of the cell cycle.
• the chemotherapeutic agent can be a cancer chemotherapeutic, a cytotoxin or combinations thereof.
• the cytotoxin can be an alkylating agent.
• the cancer chemotherapeutic can be an anti -metabolite or an anti-mitotic and can be selected from the following examples; temozolamide (Terno), 5-fluorouraciI, 6-mecaptopurine, bleomycin, carboplatin, cisplatin, dacarbazine, doxorubicin, ep ⁇ rubicin, etoposide, hydroxyurea, ifosfamide, irinotecan, topotecan, metotrexate, mitoxantrone, oxaliplatin, pacUtaxel, doocetaxol, vinblastine, vincristine, vinorelbine, vindesine, mitomycin C and combinations thereof.
• the dosage of at least one chemotherapeutic agent can be administered before, after or during a dosage of radiation.
• the dosage of radiation can be administered before, after or during a dosage of at least one chemotherapeutic.
• the period between the first administration of the cell cycle inhibitor and the cytotoxin allows the accumulation of cells at G & /S of the cell cycle. This method increases the percentage of the cells which are in the S or M phase, thereby increasing the effectiveness of the dosage of at least one chemotherapeutic agent, the dosage of radiation, or the dosage of both and subsequently reducing the toxic load required to kill a predetermined amount of eukaryotic cells.
• the cell cyc!e inhibitor can be administered a second time, after the administration of the dosage of at least one chemotherapeutic agent, the dosage of radiation, or the dosage of both to slow re-growth of targeted cells or tumors so that further administrations of the dosage can be provided as needed.
• This second administration of a cell cycle inhibitor will resynchronize a percentage of the population of cells at G
• the cell cycle inhibitor can be administered through several routes including parenteral, intravenous, intramuscular, intraperitoneal, intrathecal, suppository, transdermal, topical, or oral. Oral administration of the cell cycle inhibitor is most preferred.
• An oral administration can be administered as a dosage unit, typically a pill or capsule along with a pharmaceutically acceptable carrier.
• the T type calcium channel inhibitors restrict the influx of extracellular calcium into the cell which is critical for a number of vital cellular processes.
• the calcium necessary for these processes comes from the extracellular milieu via influx through calcium channels.
• Calcium channels are grouped into several families based upon sequence analysis, biophysical characteristics and pharmacological sensitivity. These calcium channels have been implicated in regulation of blood pressure, cardiac rhythm and cellular proliferation. Studies also suggest that T-type calcium channels may play an important role in age related macular degeneration. At least one pharmacological agent, rnibefradil, has been proven to be clinically effective because of inhibition of T channel function. Inhibitors of calcium entry are useful for treating hypertension, cardiac arrhythmia and clinically deleterious cellular proliferation.
• T type calcium channels are present in cells, cell lines and specifically cancer cell lines. Specifically, the Cav3.2 isoform of T type calcium channels has been shown to be aberrantly expressed in breast cancer tissue as compared to normal adjacent breast tissue in Japanese women, as discussed in reference Asaga, S., Ueda, M., Jinno, H., Kikuchi, K., Itano, O., Ikeda, T., and Kitajima, M. (2006) Anticancer Res 26, 35-42. [0030] Cell cycle inhibitors effectively stop or slow progression of eukaryotic cells at cell cycle checkpoints, including G
• a dosage of at least one chemotherapeutic agent, a dosage of radiation, or a dosage of both is administered to kill a proportion of cells in the S.
• killed is meant that the cell undergoes apoptosis or necrosis.
• the specific dosage of at least one chemotherapeutic agent, dosage of radiation, or dosage of both will be dictated by clinical experience of one skilled in the art, where different diseases are treated with different dosages and different agents. For exemplary pyramides only, the following dosages of chemotherapeutic agents may be used to treat the following diseases. In treating glioblastoma, the cytotoxin tcmozolamide may be used.
• the cytotoxin melphalan or temozolamide may be used.
• the cytotoxin gemcilabine may be used.
• the cytotoxin gemcitabine may be used.
• the cytotoxin irinotecan or 5-fluorouracil may be used.
• This interlaced therapy i.e. administration of cell cycie inhibitors followed by administration of a dosage of at least one chemotherapeutic agent, a dosage of radiation, or a dosage of both can be used to reduce the progression, proliferation or growth of a disease or condition, as explained more thoroughly in Examples 4 and 5 below.
• the same dosage of at least one chemotherapeutic agent, dosage of radiation, or dosage of both is more effective as compared to a chemotherapeutic or radiation dosage when used alone.
• T channel calcium channel blockers mibefradil (m ⁇ b), nickel (Ni) or TTL-1 177 (a proprietary compound owned by the assignee Tau Therapeutics), before adding nocodazole. Absent an effect on the T channel blockers, cells would be locked at the cell cycle checkpoint between G 2 and M by nocodazole as happened with cells treated with it alone. Instead, treatment with the T type calcium channel blockers arrested cells at the cell cycle checkpoint between Go and Gi and prevented accumulation at the cell cycle checkpoint between G 2 and M that would otherwise have resulted from nocodazole. This shows that T type calcium channel blockers arrest cycling cells at Gj/S.
• mice which were originally treated with mibefradil.
• a pooled, two tailed Student's t-test over all seven tumor volume measurements yielded p 0,0329.
• the mean volume in the control group, which received no intervention was 1214 mm with three animals euthanized because of tumor size.
• mice treated with temozolamide alone had tumors with a mean volume of 156 ⁇ 65 mm 3 vs. a volume of 70 ⁇ 19 mm 3 for animals treated with mibefradil and temozolamide.
• the differences in volume indicate that mice treated with interlacing therapy have tumors about 55% smaller than mice treated with only a cytotoxin over 30 days.

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