WO2001045740A2 - Compositions et procedes de traitement du cancer du sein - Google Patents

Compositions et procedes de traitement du cancer du sein Download PDF

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WO2001045740A2
WO2001045740A2 PCT/US2000/035315 US0035315W WO0145740A2 WO 2001045740 A2 WO2001045740 A2 WO 2001045740A2 US 0035315 W US0035315 W US 0035315W WO 0145740 A2 WO0145740 A2 WO 0145740A2
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cancer
estrogen receptor
tamoxifen
cells
subject
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PCT/US2000/035315
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WO2001045740A3 (fr
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Geoffrey Clark
Joanne Zujewski
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The Government Of The United States, Department Of Health And Human Services
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Priority to AU22928/01A priority Critical patent/AU2292801A/en
Publication of WO2001045740A2 publication Critical patent/WO2001045740A2/fr
Publication of WO2001045740A3 publication Critical patent/WO2001045740A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compositions and methods for treating and/or preventing cancer.
  • the present invention provides compositions and methods for the treatment and/or prevention of breast cancer.
  • the present invention provides combination drug therapy that acts in a synergistic manner to inhibit the growth of cancer cells (e.g., breast cells).
  • cancer cells e.g., breast cells.
  • therapeutic agents are administered to subjects suspected of having cancer or being susceptible to cancer, subjects with cancer, subjects experiencing a recurrence of cancer, or subjects who are post-operative for cancer. It is also contemplated that the treatment agents be prophylactically administered to patients at risk for development of cancer.
  • in situ carcinomas Due to the increased use of screening mammography and heightened breast cancer awareness in the public, in situ carcinomas presently account for 20% of newly diagnosed cases of breast cancer, with the majority being ductal carcinoma in situ (DCIS). These lesions are associated with a risk of approximately 30% for subsequent invasive breast cancer in the ipsilateral breast. As the risk of metastasis in DCIS cases is relatively small, management decisions are largely centered on the involved breast. The traditional therapy, total mastectomy, has a highly likelihood of cure. However, breast conservation may be appropriate for many women with DCIS. Lumpectomy, in combination with radiotherapy has been shown to reduce the likelihood of recurrence of in situ or invasive breast cancer in these individuals.
  • the present invention relates to compositions and methods for treating and/or preventing cancer.
  • the present invention provides compositions and methods for the treatment and/or prevention of breast cancer.
  • the present invention provides combination drug therapy that acts in a synergistic manner to inhibit the growth of cancer cells (e.g., breast cells).
  • cancer cells e.g., breast cells.
  • therapeutic agents are administered to subjects suspected of having cancer or being susceptible to cancer, subjects with cancer, subjects experiencing a recurrence of cancer, or subjects who are post-operative for cancer. It is also contemplated that the treatment agents be prophylactically administered to patients at risk for development of cancer.
  • the present invention provides compositions comprising at least one selective estrogen receptor modulator and at least one famesyl transferase inhibitor.
  • the composition is therapeutically effective in that the cancer cells are killed.
  • the composition is capable of inhibiting the growth of cancer cells expressing estrogen receptors (i.e., the composition is anti-proliferative).
  • the present invention also provides methods of treatment of cancer. In one embodiment, the methods comprise providing: i) a subject suffering from cancer, ii) at least one selective estrogen receptor modulator and iii) at least one famesyl transferase inhibitor; and b) administering the selective estrogen receptor modulator and famesyl transferase inhibitor to the subject.
  • the subject is suffering from breast cancer, while in other embodiments the subject is at risk for developing cancer, and in still other embodiments, the subject is experiencing a recurrence of cancer.
  • the cancer cells of the subject express estrogen receptors.
  • the selective estrogen receptor modulator is tamoxifen.
  • the selective estrogen receptor modulator and famesyl transferase inhibitor are provided in a combination composition such that they are administered together.
  • the selective estrogen receptor modulator and fa esyl transferase inhibitor are provided to the subject in separate compositions, such that they are administered to the subject sequentially.
  • the selective estrogen receptor modulator and famesyl transferase inhibitor are provided in a single dosage unit (e.g., in a single tablet, pill, or liquid dose), while in other embodiments they are provided in separate units (e.g., each compound is provided in a separate pill, tablet, or liquid fo ⁇ nulation). In still further embodiments, the selective estrogen receptor modulator and/or the famesyl transferase inhibitor are provided in sub-therapeutic concentrations.
  • Figure 1 is a graph showing results obtained for MCF7 cells.
  • Figure 2 is a graph showing the results obtained for T47D cells.
  • Figure 3 is a graph showing that tamoxifen and FTI did not act synergistically to inhibit growth of MDA-231 cells.
  • selective estrogen receptor modulator refers to the class of compounds that is capable of binding to the estrogen receptor. It is not intended that the definition be limited to any particular compound. Indeed, it is contemplated that any number of such modulators will find use in the present invention.
  • tamoxifen refers to the selective estrogen receptor modulator commonly referred to as tamoxifen, as well as by its tradename “Nolvadex.” Tamoxifen is a mixed estrogen agonist-antagonist. The major mode of action of the compound is through its interaction with the estrogen receptor.
  • famesyl transferase inhibitor and “FTI” refer to compounds capable of inhibiting the effects of famesyl transferases (also referred to as “famesyl protein transferases”).
  • chemotherapeutic agent refers to an agent that inhibits the growth or decreases the survival of neoplastic or pathogenic microbial cells or inhibits the propagation (which includes without limitation replication, viral assembly or cellular infection) of a virus. It is intended that the definitions encompass compounds purified from the natural source, as well as compounds prepared synthetically or by semisynthesis. Thus, it is not intended that the present invention be limited to these compounds produced in by a particular method or from any specific source.
  • the temi "pharmaceutical composition” refers to any composition or compound suitable for administration to a subject for treatment and/or prevention of disease. It is contemplated that such compositions encompass drugs that are effective in reducing or eliminating signs and symptoms of disease.
  • the pharmaceutical compositions of the present invention are provided as compositions comprising at least one SERM and at least one FTI that are capable of acting synergistically to suppress the growth of cancer cells.
  • the compositions comprising at least one SERM and at least one FTI are capable of acting synergistically to kill cancer cells. It is not intended that the present invention be limited to any particular dosage or administration strategy. It is also intended that the term encompass various regimens, including, but not limited to regimens in which at least one SERM and at least one FTI are provided in separate vehicles (e.g., separate tablets, pills, liquids, etc.).
  • terapéuticaally effective amount refers an amount of a therapeutic agent that inhibits the growth or decreases the survival of neoplastic cells.
  • subtherapeutic amount and “subtherapeutic concentration” refer to an amount of a therapeutic that is administered at a concentration that would not be expected to exhibit anti-tumor effects.
  • subtherapeutic amounts of at least one selective estrogen receptor modulator and at least one famesyl transferase inhibitor are provided in conjunction with each other. The combination of these subtherapeutic concentrations of at least one selective estrogen receptor modulator and at least one famesyl transferase inhibitor act synergistically such that an anti-tumor effect is produced.
  • anti-proliferative refers to a therapeutic agent that suppresses or inhibits the growth of abnormal (e.g., tumor, malignant, or transformed) cells, but does not necessarily kill the cells.
  • cytotoxic drug or agent refers to a therapeutic agent useful in treating cancer that results in the death of cancer cells. In some preferred embodiments, cytotoxic drugs are particularly effective against rapidly dividing cells.
  • IC 50 refers to the concentration at which 50% cytotoxicity is obtained. Cytotoxicity can be measured by the method of Alley et al, Cancer Res. 48: 589-601, 1988 or Scudiero et al, Cancer Res., 48:4827, 1988, or by any other suitable method known in the art. In one embodiment, cytotoxicity can be measured based on the drug concentration at which a 50% reduction in the activity of mitochondrial enzymes is observed.
  • the term "subject” refers to a human or other animal that is capable of being treated with a pharmaceutical composition.
  • cancer refers to a neoplasm characterized by the uncontrolled growth of anaplastic cells that tend to invade surrounding tissue and/or to metastasize to distant body sites.
  • the present invention provides methods and compositions to treat and/or prevent breast cancer.
  • the term "suspected of having cancer” refers to a patient or subject who has been diagnosed as having cancer or tested positive in one or more tests diagnostic for cancer.
  • the term "susceptible to cancer” refers to a subject or patient having one or more ⁇ sk factors for cancer, is currently being treated for cancer, or is in remission from a previously diagnosed cancer
  • post-operative for removal of a cancer means the pe ⁇ od of time after a tumor has been removed from a subject
  • the term "recurrence of cancer” refers to a subject who is experiencing the recurrence of a cancer The term encompasses recurrences of the same type of cancer (e g , the same cell types are affected), as well as a second or subsequent episode of cancer in a subject in which different cell type(s) are involved
  • the term “biological agent” refers to an agent that is useful for diagnosing or imaging or that can act on a cell, organ or organism, including but not limited to drugs (e g , pharmaceuticals) to create a change in the functioning of the cell, organ or organism
  • agents can include, but are not limited to nucleic acids, polynucleotides, antibacterial agents, antiviral agents, antifungal agents, anti-parasitic agents, tumo ⁇ cidal or anti-cancer agents, proteins, toxins, enzymes, hormones, neurotransmitters, glycoproteins, immunoglobulins, immunomodulators, dyes, radiolabels, radio
  • the present invention relates to compositions and methods for treating and/or preventing cancer.
  • the present invention provides compositions and methods for the treatment and/or prevention of breast cancer.
  • the present invention provides combination drug therapy that acts in a synergistic manner to inhibit the growth of cancer cells (e.g., breast cells).
  • cancer cells e.g., breast cells.
  • therapeutic agents are administered to subjects suspected of having cancer or being susceptible to cancer, subjects with cancer, subjects experiencing a recurrence of cancer, or subjects who are post-operative for cancer. It is also contemplated that the treatment agents be prophylactically administered to patients at risk for development of cancer.
  • SERMs Selective Estrogen Receptor Modulators
  • SERMs selective estrogen receptor modulators
  • SERM encompasses numerous pharmaceuticals, including phytoserms (i.e., phytoestrogens), and environmental pollutants (xenoestrogens or "xenoserms").
  • Tamoxifen acts a competitive inhibitor of estradiol binding to the estrogen receptor.
  • tamoxifen When bound to the estrogen receptor, tamoxifen induces a change in the receptor's three-dimensional shape, which inhibits its binding to the estrogen-responsive element (ERE) on DNA.
  • EEE estrogen-responsive element
  • TGF- ⁇ transforming growth factor ⁇
  • IGF-1 insulin-like growth factor 1
  • tamoxifen remains the endocrine treatment of choice for women with hormone receptor-positive breast cancer and those with a high risk of disease recurrence.
  • the presence of estrogen receptors is the best predictor for a response to endocrine therapy.
  • Approximately half of the patients with estrogen receptor positive tumor cells will respond to tamoxifen therapy, while less than 15% of those with estrogen receptor-negative cells will respond (Goodman and Gilman, supra).
  • tamoxifen is also used in premenopausal women with estrogen receptor- positive cells, other alternatives may also be used that help eliminate ovarian estrogen production.
  • tamoxifen lowers the total serum cholesterol, LDL cholesterol, and lipoproteins, and raises apolipoprotein Al levels, potentially decreasing the risk of myocardial infarction in patients taking the drug.
  • tamoxifen may help slow the development of osteoporosis in postmenopausal women. While the side effects are minimal in comparison with many other cancer therapies, high doses of tamoxifen have been associated with retinal degeneration. The most frequent adverse reactions include hot flashes, nausea, and vomiting.
  • tamoxifen therapy there are other potential side effects associated with tamoxifen therapy, including an increased risk of thromboembolic events, the occurrence of retinal deposits, decreased visual acuity, and cataracts
  • tamoxifen acts as a hepatic carcinogen in animals, although increases m pnmary hepatocellular carcinoma have not been reported in patients (Goodman and Gilman, supra)
  • SERMs without these potentially se ⁇ ous side effects will find use m the present invention.
  • FTI Farnesyl Transferase Inhibitors
  • Ras proteins are plasma membrane-associated GTPases that function as relay switches m the transduction of biological information from extracellular signals to the cell nucleus In normal cells, these proteins cycle between the inactive (GDP) and active (GTP)-bound forms in the regulation of cellular proliferation and differentiation Va ⁇ ous t ⁇ ggers are involved in this process
  • GDP inactive
  • GTP active
  • Va ⁇ ous t ⁇ ggers are involved in this process
  • Ras is locked in its GTP -bound form due to ammo acid mutations
  • the enzymes in the pathway e g , Raf, MEK, and MAPK
  • oncogenic Ras must associate with the plasma membrane to cause malignant transformation.
  • This post-translational modification is vital for the function of Ras proteins, as without it the Ras protein cannot stably associate with the plasma membrane and loses the ability to transform cells Ras membrane association is mediated through a se ⁇ es of post-translational modifications
  • the first step in this se ⁇ es is catalyzed by a cytosohc heterodimer farnesyl transferase (FTase), which attaches farnesyl to the thiol group of cysteine of the carboxyl-terminal tetrapeptide CAAX, where "A" is isoleucine or vahne, and "X" is se ⁇ ne or methionme Because farnesylation is required and sufficient for Ras transformation, FTAse has been considered a target for the development of a new class of anti-cancer agents Although CAAX peptides are potent competitive inhibitors of FTase, their rapid degradation and low cellular uptake have limited their use as therapeutic agents (See, Lemer et al, J.
  • FTIs are a class of designed drugs that were specifically developed to inhibit the Ras oncogene.
  • a striking characteristic and significant advantage of this class of compounds is the lack of toxicity associated with the compounds (i.e., as observed in most model systems).
  • the anti-tumor activity exhibited by FTIs is largely Ras-independent. This hypothesis is based on two observations. First, the kinetics of inhibition of transformation do not follow the kinetics of Ras de-famesylation. Second, the ability of FTIs to inhibit the soft agar growth of a particular tumor cell line appears to have no correlation with its Ras mutation status. Thus, the true mechanism of FTI function remains to be elucidated. Nonetheless, an understanding of the mechanism of action of FTIs is not necessary in order to make and use the present invention. Moreover, a variety of different FTI compounds have been proven effective in model studies and are now in clinical trials.
  • FTI can cooperate with taxol (paclitaxel) to inhibit tumor growth in some cell lines (Sepp-Lorenzino et al, supra), until the development of the present invention, the synergistic effect of FTIs and SERMs was not known. As FTIs typically exhibit an unusually low toxicity in animal studies, these compounds were used in the development of the present invention in combination with other anti-cancer compounds, including those that inhibit estrogen receptor positive cells (e.g., tamoxifen).
  • the combination of tamoxifen and FTI was found to act synergistically in inhibiting the growth of cells positive for estrogen receptors (e.g., MCF7 cells).
  • the surprising observation was made that the combination of tamoxifen and FTI synergistically inhibited the growth of cells resistant to FTI inhibition of transformation (e g., T47D cells).
  • the combination of tamoxifen and FTI did not exhibit synergistic inhibition of cells negative for estrogen receptors (e g , MDA-231 cells) It is contemplated that the combination therapy of the present invention will provide significant advantages m the treatment of breast cancer, as compared to the administration of SERMs or FTIs alone.
  • the present invention will find use m treatment regimens that involve the use of lower doses of SERMs or a shorter duration of SERM (e.g., tamoxifen) treatment. It is contemplated that the efficacy of the compositions of the present invention be demonstrated in an animal model. For example, a mu ⁇ ne mammary carcinoma model is implemented to demonstrate the effectiveness of combination therapy with famesyl transferase inhibitors and selective estrogen receptor modulators It is further contemplated that pharmacokinetics studies be performed in healthy animals (e.g., mice)
  • the present invention encompass administration of at least one SERM and at least one FTI either as a single composition (i.e., both compounds are present in the same composition) or in the alternative, in separate compositions. It is also not intended that the present invention be limited to the administration of at least one SERM and at least one FTI at the same time, as it is contemplated that these compounds may be administered to subjects in a sequential manner (e g , one composition is taken as the morning dose and the other composition is taken as the evening dose). In addition, it is contemplated that sequential administration encompasses other treatment regimens.
  • one compound e.g., at least one SERM or at least one FTI
  • a certain time period e.g., days, weeks, or months
  • the other compound i.e., at least one SERM or at least one FTI
  • each of these compounds will be given in conjunction with other compounds as appropriate for each individual subject.
  • various other agents may be incorporated into the combination composition of the present invention.
  • various other therapeutic agents e.g., growth factors, vitamins, nutrients, nutritional supplements, receptor agonists and/or antagonists, etc.
  • stabilizers, detectable molecules, and the like will find use in certain embodiments of the present invention.
  • compositions including the SERM and FTI combinations of the present invention be accomplished orally or parenterally.
  • Methods of parenteral delivery include topical, intra-arterial (e.g., directly to a tumor), intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and other compounds that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Further details on techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences” (Maack Publishing Co, Easton PA).
  • compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration.
  • Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • compositions for oral use can be obtained through combination of active compounds with solid excipient, optionally g ⁇ nding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores
  • suitable excipients such as carbohydrate or protein fillers include, but are not limited to sugars, including lactose, sucrose, manmtol, or sorbitol, starch from com, wheat, ⁇ ce, potato, or other plants, cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose, and gums including arable and tragacanth, as well as proteins such as gelatin and collagen
  • disintegrating or solubilizmg agents may be added, such as the cross-linked polyvmyl pyrrohdone, agar, algimc acid, or a salt thereof, such as sodium algmate
  • Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arable, talc, polyvmylpyrrohdone, carbopol gel, polyethylene glycol, and or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to charactenze the quantity of active compound (i e , dosage)
  • suitable coatings such as concentrated sugar solutions, which may also contain gum arable, talc, polyvmylpyrrohdone, carbopol gel, polyethylene glycol, and or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to charactenze the quantity of active compound (i e , dosage)
  • Push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol
  • Push-fit capsules can contain active ingredients mixed with a filler or binders such as lactose or starches, lub ⁇ cants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • penetrants appropriate to the particular barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • the compositions of the present invention may be manufactured in a manner that known in the art (e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes).
  • the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.
  • the preferred preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
  • pharmaceutical compositions comprising a compound of the invention formulated in an acceptable carrier have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition.
  • labeling would include amount, frequency and method of administration.
  • Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
  • the therapeutically effective dose can be estimated initially either in cell culture assays or in any appropriate animal model.
  • the animal model is also used to achieve a desirable concentration range and route of administration Such information can then be used to determine useful doses and routes for administration in humans.
  • the sub-therapeutically effective dose optimally suited for va ⁇ ous embodiments of the present invention is also determined.
  • the subtherapeutic doses of SERM(s) and/or FTI(s) for optimal synergistic effect in vivo and in vitro are also determined
  • a therapeutically effective dose refers to that amount of protein or its antibodies, antagonists, or inhibitors which ameliorate the symptoms or condition
  • Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or expe ⁇ mental animals (e g , ED 50 , the dose therapeutically effective in 50% of the population; and LD 50 , the dose lethal to 50% of the population)
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD 50 /ED 50
  • Pharmaceutical compositions which exhibit large therapeutic indices are preferred
  • the data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity
  • the dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration
  • the present invention also encompasses compositions that are administered at subtherapeutic concentrations For example, it is contemplated that
  • compositions might be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • Guidance as to particular dosages and methods of delivery is provided in the literature (See, US Patent Nos. 4,657,760; 5,206,344; and 5,225,212, each of which is herein incorporated by reference).
  • EXAMPLE 1 Inhibition of Cell Growth by Tamoxifen and FTI
  • Three cell lines were used, including two estrogen receptor positive lines and one estrogen receptor negative line.
  • the cell lines, their estrogen receptor status, and sensitivity to tamoxifen and FTI are shown in Table 1, below, obtained from the ATCC (HTB-26 [MDA-MB-231)], HTB-22 [MCF7], and HTB-133 [T-47D]). TABLE 1. Cell Lines Tested
  • T47D and MCF7 are estrogen receptor positive, they are both sensitive to inhibition by tamoxifen, which works at least primarily, by blocking the estrogen receptor.
  • T47D cells have previously been shown to be resistant to the effects of FTI compounds (Sepp-Lorenzino et al, Cancer Res., 55:5302-5309 [1995]).
  • MDA-231 cells have lost expression of the estrogen receptor. Thus, they are resistant to the effects of tamoxifen. These cells are also reported to be resistant to FTI (Sepp- Lorenzino et al, supra).
  • the cell lines were all grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, as well as penicillin/streptomycin (10 units/ ⁇ l penicillin and 10 ⁇ g/ml streptomycin) and insulin (10 ⁇ g/ml). Cells were grown as monolayers in 6 well plates at 2 x 10 5 cells per well and allowed to grow for 48 hours before commencing drug treatment. Tamoxifen was dissolved in water to a final concentration of 5 ⁇ g/ml. FTI-277 (Lemer et al, J. Biol.
  • DMSO dimethylsulfoxide
  • DTT dithiothreitol
  • Figure 1 shows the effects of tamoxifen and FTI, alone and in combination on the growth of MCF7 cells.
  • the data shown in Figure 1 represent the average of three experiments. The standard error was within 20%.
  • column 1 provides the results for the carrier alone (DMSO DTT), while column 2 provides the results for tamoxifen and carrier, column 3 provides the results for FTI alone, and column 4 provides the results for tamoxifen and FTI.
  • the growth of MCF7 cells was also inhibited by the combination of tamoxifen and FTI in a synergistic manner.
  • Figure 2 shows the effects of tamoxifen and FTI, alone and in combination on the growth of T47-D cells.
  • the data shown in Figure 2 represent the average of three experiments. The standard error was within 20%.
  • column 1 provides the results for the carrier alone (DMSO/DTT)
  • column 2 provides the results for tamoxifen and carrier
  • column 3 provides the results for FTI alone
  • column 4 provides the results for tamoxifen and FTI.
  • DMSO/DTT carrier alone
  • FTI FTI alone
  • column 4 provides the results for tamoxifen and FTI.
  • the tamoxifen/FTI combination acted synergistically in T47-D cells. This cell line was included in these experiments as it had been reported to be resistant to FTI action (Sepp-Lorenzino et al, supra).
  • Figure 3 shows that the combination of tamoxifen and FTI did not act synergistically in decreasing the growth of MDA-231 cells.
  • the data shown in Figure 3 represent the average of two experiments and the standard error was within 20%.
  • the MDA-231 cells were assayed as a control cell line, as these cells are highly transformed and very metastatic. They are no longer dependent upon stimulation of the estrogen receptor for their growth and do not express the receptor protein. Consequently, they are immune to tamoxifen inhibition.
  • the combination compositions of the present invention provide an improved system for the synergistic action of therapeutic agents such as famesyl transferase inhibitors and selective estrogen receptor modulators for treatment of cancer cells that express estrogen receptors.

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Abstract

La présente invention concerne des compositions et des procédés permettant de traiter et/ou prévenir le cancer. En particulier, la présente invention traite de compositions et de procédés pour traiter et/ou prévenir le cancer du sein. De manière spécifique, l'invention a pour objet une thérapie d'association de médicaments qui agit par synergie pour inhiber la croissance des cellules cancéreuses (par exemple, les cellules du sein). Dans certains modes de réalisation, des agents thérapeutiques sont administrés à des sujets suspectés de présenter un cancer ou prédisposés à cette maladie, ou présentant un cancer récidivant ou qui viennent d'être opérés d'un cancer. L'invention envisage également d'administrer les agents de traitement à des patients présentant un risque de cancer.
PCT/US2000/035315 1999-12-22 2000-12-20 Compositions et procedes de traitement du cancer du sein WO2001045740A2 (fr)

Priority Applications (1)

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AU22928/01A AU2292801A (en) 1999-12-22 2000-12-20 Compositions and methods for treatment of breast cancer

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US17192899P 1999-12-22 1999-12-22
US60/171,928 1999-12-22

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WO2001056552A2 (fr) * 2000-02-04 2001-08-09 Janssen Pharmaceutica N.V. Inhibiteurs de la farnesyl proteine transferase pour le traitement du cancer du sein
CN100537542C (zh) * 2002-02-27 2009-09-09 先灵公司 用作抗肿瘤剂的法呢基蛋白质转移酶抑制剂
EP2269603B1 (fr) 2001-02-19 2015-05-20 Novartis AG Traitement des tumeurs du sein avec un dérivé de la rapamycine en association avec l'exémestane
CN113559222A (zh) * 2021-09-14 2021-10-29 临沧宏胜生物科技开发有限公司 一种抑制乳腺癌细胞转移的中药组合物及其制备方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056552A2 (fr) * 2000-02-04 2001-08-09 Janssen Pharmaceutica N.V. Inhibiteurs de la farnesyl proteine transferase pour le traitement du cancer du sein
WO2001056552A3 (fr) * 2000-02-04 2002-04-25 Peter Albert Palmer Inhibiteurs de la farnesyl proteine transferase pour le traitement du cancer du sein
EP2269603B1 (fr) 2001-02-19 2015-05-20 Novartis AG Traitement des tumeurs du sein avec un dérivé de la rapamycine en association avec l'exémestane
CN100537542C (zh) * 2002-02-27 2009-09-09 先灵公司 用作抗肿瘤剂的法呢基蛋白质转移酶抑制剂
CN113559222A (zh) * 2021-09-14 2021-10-29 临沧宏胜生物科技开发有限公司 一种抑制乳腺癌细胞转移的中药组合物及其制备方法

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