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• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to chemotherapeutic strategies for the treatment of cancer wherein retinoic acid receptor (RAR) ligands, in particular ⁇ / ⁇ selective agonists or RAR pan antagonists, are administered in combination with tubulin polymerizing agents such as taxanes.
• RAR ⁇ / ⁇ selective agonists and RAR pan antagonists are effective anti-cancer agents and exhibit reduced toxicity as compared to RAR pan agonists which also activate RAR ⁇ and natural retinoids such as all trans retinoic acid which activate RAR ⁇ and RXR.
• RAR ⁇ / ⁇ selective agonists and RAR pan antagonists act synergistically with tubulin polymerizing agents, particularly taxanes, dramatically lowering the effective dose of taxane required to induce cytotoxicity of a wide range of tumor cell lines. It is believed that the synergy with RAR ⁇ / ⁇ selective agonists is related in part to effects on Bcl-2 expression/phosphorylation as well as the activity of the JNK and API. Accordingly, similar synergies with RAR ⁇ / ⁇ selective agonists are also expected with other agents which increase phosphorylation of Bcl-2. Background of the Invention
• the retinoids are biologically active derivatives of vitamin A that mediate a wide range of physiologic functions during both embryogenesis and adult life (Vitamin A in Health and Disease. Ed. Blomhoff, Institute for Nutrition Research, University of Oslo, Oslo Norway, 1994; Kastner et al . Cell 1995 83:859-869; Giguere et al . Ann. N.Y. Acad. Sci. 1996 785:12-22).
• the natural retinoids primarily consist of all trans retinoic acid (ATRA) and 9-cis retinoic acid, which are processed from vitamin A through its irreversible oxidation (Vitamin A in Health and Disease. Ed.
• retinoid ligands can regulate the proliferation, differentiation and apoptosis of a wide variety of both normal and malignant cells (Vitamin A in Health and Disease. Ed. Blomhoff, Institute for Nutrition Research, University of Oslo, Oslo Norway, 1994; Lotan, R. Sem. in Cancer Biol . 1991 2:197-208; Love, J.M. and Gudas , L.J. Curr. Opinion in Cell Biol. 1994 6:825-831; Lotan, R. Faseb J. 1996 10:1031-1039; and Fitzgerald et al . Cancer Res. 1997 57:2642-2650).
• RARs retinoic acid receptors
• RXRs retinoid X receptors
• RAR and RXR are members of the nuclear hormone receptor (NHR) superfa ily and act as ligand-dependent transcription factors, which can modulate target gene expression by binding as RAR/RXR heterodimeric complexes to the specific retinoid response element (RARE) DNA sequence, which consists of direct repeats of the consensus sequences PuG(G/A) (T/A)CA (n) ⁇ _ 5 PuG(G/T)TCA (Gronemeyer, H., and Moras, D. Nature 1995 375:190-191).
• the activity of the RAR/RXR heterodimer can be repressive or stimulatory, depending upon its apo- (unliganded) or holo- (ligand-bound) conformation, respectively.
• the apo-conformation of RAR/RXR heterodimers is a permissive structure allowing protein interaction interfaces to initiate large corepressor multi-protein complex formation including the recruitment of NCOR and histone deacetylases which together maintain the chromatin in a condensed transcriptionally inactive structure to repress target gene expression (Xu et al . Curr. Opinion in Genetic and Development 1999 9:140- 147; Hu, X. and Lazar, M.A. Trends in Endocrin. and Metab. 2000 11:6-10; Robyr et al . Mol. Endocrin. 2000 14:329-347).
• the binding of agonist ligand to RARs is associated with a conformational transition of the ligand binding domain (LBD; Renaud et al . Nature 1995 378:681-689) resulting in the destabilization of the corepressor complex and simultaneous recruitment of coactivators, including pl60 protein family, CBP/p300 and the multiprotein complexes TRAP/DRIP/ARC .
• coactivators including pl60 protein family, CBP/p300 and the multiprotein complexes TRAP/DRIP/ARC .
• Some of these factors contain histone acetyltransferase activity allowing the decondensation of the chromatin required for the subsequent link of the holo-RAR/RXR heterodimer with the basal transcriptional complex to initiate target gene expression (Xu et al. Curr.
• ATRA and synthetic retinoid receptor ligands have been shown to promote tumor regression in a number of animal models of carcinogenesis and have shown efficacy in patients afflicted with acute promyelocytic leukemia (Chomienne et al . Faseb J 1996 10:1025-1030; Fenaux et al . Leukemia 2000 14:1371-1377).
• the RAR agonist, ALRT1550, potent inhibitor of API has also been included in a phase I/II study on a heterogeneous population of 15 patients with advanced cancer, including non-small cell lung, thyroid, kidney, uterine leiomyosarcoma, prostate and adenoid cystic carcinoma (Soignet et al . Proc . Annu . Meet. Am. Soc. Clin. Oncol. 1998 17:A826).
• Cytosine arabinoside in combination with paclitaxel and ATRA was also suggested as a combination chemotherapy for acute myeloblastic leukemia. More recently, ATRA has been shown to sensitize breast cancer cell lines to the cell killing effects of paclitaxel and Adriamycin (Wang et al. Cancer Res. 2000 60:2040-2048).
• ATRA, 13cis retinoic acid, and ALRT1550 are all RAR pan agonists, meaning that they target and activate the ⁇ , ⁇ , and ⁇ RAR isotypes. Further, ATRA is converted in si tu into 9cis-RA which is a pan RAR and RXR agonist.
• RAR ⁇ -2 arises from alternative promoter use of the RAR ⁇ gene promoter P2 (Chambon, P. Sem. In Cell Biol. 1994 5:115-125), which contains a strong RARE suggesting that RAR ⁇ expression is upregulated by retinoic acid and places RAR ⁇ 2 as a potential target gene underlying the growth suppressive effects of retinoic acid. Consistent with a role in modulating cell growth, RAR ⁇ gene inactivation in F9 teratocarcinoma cells results in the loss of retinoic acid dependent growth arrest (Faria et al . J. Biol. Chem.
• RAR ⁇ and - ⁇ as well as RXR ⁇ are mostly unaltered in malignant tissues.
• mucocutaneous toxic effects of retinoids which are considered as the major toxicity induced by retinoids and limits their use as therapeutic agents is associated with
• an object of the present invention is to provide synergistic chemotherapeutic combinations for use in the treatment of cancer.
• the synergistic combination comprises a RAR ⁇ / ⁇ selective agonist and a second agent which increases phosphorylation of Bcl-2, such as a tubulin polymerizing agent, preferably a taxane.
• the synergistic combination comprises a RAR pan antagonist and a tubulin polymerizing agent, preferably a taxane .
• Another object of the present invention is to lower the effective dose of a selected cytotoxic agent required to induce cytotoxicity in tumor cells by administering the selected cytotoxic agent in combination with a RAR ⁇ / ⁇ selective agonist or RAR pan antagonist.
• Yet another object of the present invention is to provide methods of treating cancer in patients with these synergistic chemotherapeutic combinations .
• a patient is administered a RAR ⁇ / ⁇ selective agonist in combination with a second agent which increases phosphorylation of Bcl-2, such as a tubulin polymerizing agents, preferably a taxane.
• the patient is administered a RAR pan antagonist in combination with a tubulin polymerizing agent, preferably a taxane.
• Figure 1 provides a synthetic ⁇ scheme for exemplary RAR ⁇ / ⁇ selective agonists useful in the present invention.
• FIG. 2 provides a synthetic scheme for an exemplary RAR pan antagonist useful in the present invention. Detailed Description of the Invention
• the present invention relates to RAR ⁇ / ⁇ selective agonists and RAR pan antagonists and their use in synergistically enhancing tumor cell sensitivity to selected cytotoxic agents.
• RAR ⁇ / ⁇ selective agonist a compound which activates the ⁇ and ⁇ isotypes of the retinoic acid receptor but which exhibits little or no activation of, or actually inhibits, the ⁇ isotype.
• RAR ⁇ / ⁇ selective agonists useful in the present invention are depicted in general in Formula I:
• RAR pan antagonist it is meant a compound which inhibits the ⁇ , ⁇ , and ⁇ isotypes of the retinoic acid receptor.
• An exemplary RAR pan antagonist is depicted in Formula II:
• This compound can be synthesized routinely by those of skill in the art in accordance with well known methods.
• An exemplary method of synthesis for this compound is set forth in Example 2.
• other compounds exhibiting RAR pan antagonistic activity can also be used. Additional examples of RAR pan antagonists are disclosed in WO 97/48672. Other compounds with this activity can also be identified routinely by those of skill in the art in accordance with methods such as described in WO 97/48672.
• pharmaceutically acceptable salts of the compounds of Formulas I, la, lb and II are useful in the methods and compositions of the present invention.
• Such pharmaceutically acceptable salts include, but are not limited to, salts formed with alkali metals such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; organic bases such as dicyclohexylamine, tributylamine, pyridine and the like; and amino acids such as arginine, lysine and the like.
• RAR pan agonist it is meant a compound which activates the ⁇ , ⁇ and ⁇ isotypes of the retinoic acid receptors.
• RAR pan agonists include, but are not limited to, ATRA, 13cis retinoic acid, and ALRT1550. While RAR pan agonists have been reported to inhibit tumor progression, these treatments have been limited by unwanted toxicities including, but not limited to, mucocutaneous toxic effects, headaches, teratogenesis , musculoskeletal toxicity, dylipidemias , skin irritation and hepatotoxicity .
• RAR pan agonists which are considered as the major toxicity induced by these compounds and limits their use as therapeutic agents, are associated with RAR ⁇ activity.
• the natural retinoid ATRA is converted in si tu into 9cis-RA which is a pan RAR and RXR agonist. Activation of RXR following ATRA administration has also been associated with undesirable side effects.
• selected cytotoxic agent it is meant a taxane or other agent which acts by similar mechanisms to taxanes.
• this term is meant to be inclusive of other tubulin polymerizing agents.
• this term is meant to be inclusive of other agents which increase Bcl-2 phosphorylation.
• the selected cytotoxic agent is paclitaxel or docetaxel .
• RAR ⁇ / ⁇ selective agonists and RAR pan antagonists act synergistically with selected cytotoxic agents to lower the effective dose of the selected cytotoxic agent required to induce cytotoxicity in tumor cells.
• the synergistic combination comprises a RAR ⁇ / ⁇ selective agonist in combination with a second agent which increases phosphorylation of Bcl-2, such as a tubulin polymerizing agents, preferably a taxane.
• the synergistic combination comprises a RAR pan antagonist and a tubulin polymerizing agent, preferably a taxane.
• the present invention also relates to methods of treating cancer by administering to a patient a RAR ⁇ / ⁇ selective agonist or RAR pan antagonist in combination with a selected cytotoxic agent.
• the RAR ⁇ / ⁇ selective agonist or RAR pan antagonist be administered in combination with a tubulin polymerizing agent, most preferably a taxane.
• the selected cytotoxic agent may also comprise an agent which increases phosphorylation of Bcl-2.
• cancer it is meant to include tumors, neoplasias, and any other malignant tissue or cells.
• the present invention also relates to pharmaceutical compositions comprising a selected cytotoxic agent and a RAR ⁇ / ⁇ selective agonist or RAR pan antagonist.
• the selected cytotoxic agent comprises a tubulin polymerizing agent, most preferably a taxane.
• compositions comprising a selected cytotoxic agent comprises a tubulin polymerizing agent, most preferably a taxane.
• the selected cytotoxic agent may also comprise an agent which increases phosphorylation of Bcl-2.
• compositions of the present invention may comprise both components in a single pharmaceutically acceptable formulation.
• the components may be formulated separately and administered in combination with one another.
• Various pharmaceutically acceptable formulations well known to those of skill in the art can be used in the present invention. Selection of an appropriate formulation for use in the present invention can be performed routinely by those skilled in the art based upon the mode of administration and the solubility characteristics of the components of the composition. For purposes of the present invention, by
• the RAR ⁇ / ⁇ selective agonist or RAR pan antagonist is administered to the patient prior to, simultaneously with, or following administration of the selected cytotoxic agent.
• the RAR ⁇ / ⁇ selective agonist or the RAR pan antagonist is administered to the patient prior to or simultaneously with the selected cytotoxic agent.
• the term "simultaneous” or “simultaneously” means that the RAR ⁇ / ⁇ selective agonist or the RAR pan antagonist and the selected cytotoxic agent are administered within 24 hours, preferably 12 hours, more preferably 6 hours, and most preferably 3 hours or less, of each other.
• RAR ⁇ / ⁇ selective agonists and RAR pan antagonists to additively or synergistically effect cell growth when administered in combination with existing chemotherapeutic agents was first assessed in three different human tumor cell lines. Inhibition of cell growth was compared in cells co-treated with paclitaxel and either a RAR pan agonist (see Formula III) , the RAR ⁇ / ⁇ selective agonist of Formula la, an RAR ⁇ agonist (see Formula IV) , an RAR ⁇ agonist (see Formula V) , an RAR ⁇ agonist (see Formula VI) , the RAR pan antagonist of Formula R pan agonist (see Formula VII) .
• the structure III through VII are depicted below:
• the RAR ⁇ / ⁇ selective agonist of Formula la dramatically lowered the effective dose of paclitaxel required to induce cytotoxicity.
• the IC 50 of paclitaxel was decreased by 8-, 15- and 32-fold in MCF7 , 0VCAR3 and SQCC-Yl cells, respectively.
• RAR ⁇ / ⁇ isotypes in the tumor-suppressive activity of the retinoids.
• the RAR pan antagonist of Formula II also lowered the effective dose of paclitaxel required to induce cytotoxicity.
• the pure RAR ⁇ agonist (Formula IV) was associated with only a 2- to 4-fold decrease in the IC 50 of paclitaxel (Table 1) , which is in agreement with its low affinity for RAR ⁇ compared to Formula la.
• efficacy is defined as percent (%) inhibition compared with DMSO .
• All IC 50 ' s are expressed in nanomolar values .
• the results are the mean of 2 to 5 experiments.
• the standard deviation associated with the IC 5 o's ranges between 10 and 20%.
• RAR pan antagonist Treatment of the MCF7 cells with a RAR pan antagonist, Formula II, also strongly impaired colony formation.
• the colonies remained small with two apparent populations of cells, one apoptotic and one in a process of differentiation, showing plasma extension. Further, pre-treatment of these cells for three days with the RAR pan antagonist significantly enhanced the sensitivity of the cells to paclitaxel.
• ATRA also impaired colony formation. However, in contrast to RAR ⁇ / ⁇ selective agonists, ATRA-treated colonies exhibited a high level of apoptosis which is believed to reflect the activity of RXR consecutive to the conversion in si tu of ATRA to 9cis-RA.
• the RAR pan antagonist did not effect Bcl-2 protein levels or paclitaxel-induced phosphorylation of Bcl-2, thus indicating that the synergy between tubulin polymerizing agents such as paclitaxel and retinoid antagonists may use a different pathway.
• the combination effect of paclitaxel and RAR ⁇ / ⁇ agonists or RAR pan antagonists on tubulin polymerization was also analyzed. Pools of soluble, non-polymerized tubulin were separated from the insoluble polymerized tubulin pool and analyzed by Western blotting using anti- ⁇ tubulin antibodies. A dose-dependent polymerization of tubulin induced by paclitaxel was observed. However, the selective RAR agonists or antagonists had no effect. Further, the combination of paclitaxel with any of the retinoids did not enhance the effect of paclitaxel alone. Thus, the retinoids do not appear to synergize with paclitaxel 's effects on the cytoskeleton to induce cytotoxicity.
• JNK Jun N-terminal Kinase
• the combination of paclitaxel with RAR ⁇ / ⁇ selective agonists enhances the paclitaxel-effect on the Jun-N-terminal kinase activity which, however, becomes uncoupled from the subsequent API transcriptional activation due to the negative cross- regulation of API induced by the retinoids.
• the cell lines used in these experiments including T47D, HT-3, UMSCC-25, MCF-7, OVCAR3 , HCT-1 16, and N-87 were obtained from ATCC and maintained in the media and serum concentration recommended by ATCC.
• H3396 cell line was obtained in accordance with the procedure set forth by Garrigues et al . (Am. J. Pathol . 1993 142:607-622), and maintained in RPMI supplemented with 10% FBS (Gibco-BRL) .
• MDA-PCA.2B and SQCC-YI were obtained from the Anderson Cancer Center (Houston, Texas) .
• A2780S and its p27 transgenic variant A2780p27, HCT-116TYPK (Taxol-resistant) and HCTVM46, SAN-1, M109 and its Taxol-resistant variant M109TX, and PAT-7 (Taxol resistant) cell lines engineered for drug resistance were also used. All the cytotoxic agents and phorbol 12-myristate 13 -acetate (PNIA) were purchased from Sigma-Aldrich. The mouse anti- ⁇ Bcl-2, anti- ⁇ -tubulin, and anti-human JNK antibodies used in these experiments were purchased from Biosource International, Sigma-Aldrich and BD-Pharmingen, respectively. The c-jun (1-169) -GST fusion protein was obtained from Upstate Biotechnology .
• Example 2 Synthetic RAR Ligands
• the RAR pan antagonist of Formula II, 4- (5 , 6-dihydro- 5, 5-dimethyl-6-oxo-8- (3 -methyl-phenyl) -anthracen-2-yl) - benzoic acid was prepared in accordance with the synthesis outlined in Figure 2 and described below.
• Cellular proliferation was quantified using [ 3 H] thymidine incorporation.
• Cells were plated in 96 well plates in media containing 10% fetal bovine serum (FBS) and allowed to adhere overnight. Cell medium was removed the following day and the indicated compounds were added to fresh medium supplemented with 10% of charcoal stripped FBS (HyClone) . Compound-containing medium was renewed after 3 days exposure. After 6 day treatment, 4 ⁇ Ci/ml of [ 3 H] thymidine (NEN Life Science Products) were added to each well for 2 to 4 hours. The cells were then trypsinized and harvested on GF/B glass fiber filters. [ 3 H] thymidine incorporated into the DNA was measured in a scintillation Topcount counter (Packard) .
• FBS fetal bovine serum
• MCF7 cells were plated in 6 well plates (500 cells/well) in DMEM supplemented with 10% FBS and grown for 5 days. The medium was then removed and the compounds were added to the medium supplemented with 5% of charcoal stripped FBS (HyClone) . The compound containing medium was renewed after 3 days and cultures were allowed to grow an additional 3 days. After 6 days exposure to compounds, colonies were stained with crystal violet. Colonies were counted to quantify colony area and number and photographed under light microscopy to assess effects on colony size and morphology. The results presented are representative of two independent experiments.
• Immunoblotting MCF-7 cellular lysates were prepared for Western blotting in accordance with procedures described by Sambrook et al . (MOLECULAR CLONING: A LABORATORY MANUAL, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)).
• Cell lysates were prepared by adding 200 ⁇ l of lysis buffer (Tris-HCl, pH 6.8, 20 mM, EDTA ImM, NP-40 0.5%) containing a protease inhibitor cocktail (Roche) to each well of 6 well plates.
• MCF7 cells were plated in 6 well plates in DMEM supplemented with 10% FBS and allowed to adhere overnight. Cell medium was removed the following day and the indicated compounds were added to fresh medium supplemented with 5% of charcoal stripped FBS
• API transcriptional activity was assessed in MCF7 cells stably transfected with (API) 5x-tk-Luc reporter gene
• (APl)5x corresponds to the collagenase gene API response element repeated 5 times in tandem
• tk is the minimal thymidine kinase promoter
• Luc the coding sequence of the luciferase gene.
• MCF7 cells were plated in 12-well plates at a density of 400,000 cells per well in DMEM supplemented with 10% FBS and allowed to adhere overnight. The next day, the medium was removed, the cells were washed with PBS and supplemented with DMEM medium containing 0.5% of charcoal stripped FBS (HyClone).
• the cells were treated for 6 hours with PMA (10 nM) in the absence or the presence of ATRA, Formula la or a RAR pan agonist of Formula III (concentrations ranging from 0.1, 1 and 50 nM) combined with or without paclitaxel (1 ⁇ M) .
• the luciferase activity was measured by using Luc-lite system from Packard according to manufacturer's recommendations. Results are expressed as percent activity compared to PMA (10 nM) which was assigned as 100% activity.
• the data presented are the mean ⁇ sem
• Immune complexes were pelleted by centrifugation 2 minutes at 10,000 rpm 4°C and washed 3 times with PBS containing 1% NP40 and 2 rtiM of Na 3 V0 4 , once with 100 M Tris-HCl pH7.5 , 0.5 M LiCl and once with Kinase Reaction Buffer (KRB: 12.5 mM MOPS pH7.5 , 12.5 mM ⁇ - glycerolphosphate, 7.5 M MgCl 2 , 0.5 mM EGTA, 0.5 mM NaF, 0.5 mM Na 3 V0 4 ) .
• KRB 12.5 mM MOPS pH7.5 , 12.5 mM ⁇ - glycerolphosphate, 7.5 M MgCl 2 , 0.5 mM EGTA, 0.5 mM NaF, 0.5 mM Na 3 V0 4
• Kinase assays were performed at 30°C for 30 minutes by resuspending the beads in 30 ⁇ l of KRB containing 5 ⁇ Ci [gamma- 33 P]ATP (NEN Life Science Products), 10 ⁇ M cold ATP, 3.3 mM DTT and 2 ⁇ g of GST-c- Jun(l-169) fusion protein.
• the kinase reaction was terminated by adding 10 ⁇ l of Laemmli sample buffer, resolved by 10% SDS-PAGE and phosphorylated GST-c-Jun visualized by autoradiography and quantified by densitometry. The results represent the mean + sem of 3 independent experiments .

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