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WO1992019765A1 - Procede de conception de traitements du cancer, procedes et compositions pharmaceutiques de traitements du cancer - Google Patents

Procede de conception de traitements du cancer, procedes et compositions pharmaceutiques de traitements du cancer Download PDF

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WO1992019765A1
WO1992019765A1 PCT/US1992/003830 US9203830W WO9219765A1 WO 1992019765 A1 WO1992019765 A1 WO 1992019765A1 US 9203830 W US9203830 W US 9203830W WO 9219765 A1 WO9219765 A1 WO 9219765A1
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drug
cells
phase
mos
morphologically transformed
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PCT/US1992/003830
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George F. Van Woude
Nicholas Schulz
Renping Zhou
Ira Daar
Marianne Oskarsson
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The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services
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Publication of WO1992019765A1 publication Critical patent/WO1992019765A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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

Definitions

  • the present invention concerns a method for
  • the present invention also concerns methods and pharmaceutical compositions for the treatment of cancer.
  • oncogenes and tumor suppressor genes belong to the hierarchy of genes that regulate these processes.
  • Oncogenes are normally positive regulators of the cell cycle and when activated, represent a gain of function in the cell. In contrast, tumor suppressor genes are negative regulators and promote transformation through their loss of function. While the number of oncogenes discovered continues to increase, the number of families to which they have been assigned has not. This may be due to the limited number of assays available for their detection, but it may also indicate that most of the families have been identified. The assignment of
  • Mitogenic stimulation of certain tyrosine kinase growth factor receptors results in specific transcriptional induction of a well-characterized series of genes, several of which are nuclear oncogenes. (Rollins et al., Adv. Cancer Res., 53. 1-32 (1989); Vogt et al.. Adv.
  • Schizosaccharomyces pombe These yeasts are as distant from each other in evolution as they are from mammals. In spite of this, certain cell cycle regulators are conserved not only in structure, but also in function. Thus, CDC28/cdc2 genes from budding and fission yeasts are functionally equivalent.
  • the product of this gene is a serine kinase whose targets are influenced during the cell cycle by the pearance of proteins termed cyclins. Cyclins, so named because of their cyclic appearance during M-phase of the cell cycle, were first discovered in clams and sea urchins. Independently, an activity termed maturation promoting factor (MPF) was discovered in unfertilized amphibian eggs (Masui et al., J. Exp.
  • MPF maturation promoting factor
  • MPF is responsible for nuclear envelope breakdown and chromosome condensation (Lohka et al., J. Cell Biol.. 98, 1222-1230 (1984); Lohka et al., J. Cell Biol.. 101. 518-523 (1985); Miake-Lye et al.. Cell. 41, 165-175 (1985)). Lohka et al. (Proc.
  • compositions for the treatment of cancer are provided.
  • the present invention is directed to a new approach for designing combinations of drugs for the treatment of cancer based on the discovery that it is desirable to use a drug which exerts its primary effect on mammalian cell cycle prior to or during S-phase in combination with a drug that exerts its primary effect on mammalian cell cycle after S-phase but prior to or during M-phase.
  • a number of drugs can be screened for their ability to interfere with the mammalian cell cycle prior to or during S-phase and drugs can also be screened for their ability to interfere with the mammalian cell cycle after S- phase but prior to or during M-phase.
  • An S-phase drug can then be used together with an M-phase drug for further screening to see if a synergistic anti- cancer effect is observed. If such an anti-cancer effect is observed, additional screening and testing on this combination can be conducted to determine whether or not the combination of drugs is therapeutically useful in a patient.
  • the two drugs can be administered to a patient (or a laboratory mammal such as a mouse, rabbit, hamster, guinea pig, etc.) at the same time as part of the same pharmaceutical composition or the two drugs can be administered to the patient in close proximity in time to each other so that a suitable level of both drugs is present in the patient whereby a synergistic effect can be achieved.
  • the two drugs will be administered to the patient within 24 hours of each other, preferably within 8 hours of each other and more preferably within 1 hour of each other. The exact timing of administration may be affected by the half-life of the drugs, the toxicity of the drugs, etc.
  • Known drugs will preferably be administered by the routes of administration and dosages currently approved by the FDA. However, when a synergistic effect is observed between two drugs, it is possible that each drug can be administered in a dosage which is lower than the dosage used when the drug is administered alone.
  • Preferred methods for combination therapy administration of drugs are intravenous
  • the doses of the S-phase drug and the M-phase drug used and the route of administration and the carriers and/or adjuvants used may vary based on the tumor type being . treated and in view of known procedures for treatment of such tumors.
  • the present invention also relates to a method for designing an anticancer treatment regimen, which
  • This method comprises selecting a first drug which acts at one checkpoint in the mammalian cell cycle; selecting a second drug which acts at a different checkpoint in the mammalian cell cycle; and testing said first and second drugs to determine if a complimentary anticancer effect is observed when the two drugs are used together.
  • This method is based on the principle that certain anticancer drugs, and in particular combinations of anticancer drugs, are effective because they take advantage of a cancer cell's inability to repair itself and/or a cancer cell's inability to check the cell cycle to ensure the proper order of cell cycle events.
  • the known check points in the cell cycle are summarized in Hartwell et al., Science, 246, 629-634 (1989). It may be desirable to use drugs which act at different checkpoints in combination therapy to treat cancer in an effort to achieve a complimentary anticancer effect which could not be achieved if the drugs were used alone or if two drugs which affect the same checkpoint are used together.
  • the present invention is also directed to a
  • compositions for treating cancer which comprises an effective cancer cell growth inhibiting amount of taxol or a taxol derivative and an effective cancer cell growth inhibiting amount of another drug which exerts its primary effect at a different point of the mammalian cell cycle, preferably prior to or during S-phase.
  • the taxol derivatives useful in accordance with the present invention are preferably water-soluble taxol derivatives. Examples of suitable taxol derivatives are described in U.S. Patent 4,942,184 to Haugwitz which issued on July 17, 1990.
  • Suitable treatment regimens for such a pharmaceutical composition include a variety of administrative routes as described above, for example, infusion over suitable time periods at suitable doses, e.g., 170-300 mg/m 2 /cycle.
  • the present invention is also directed to a method for testing whether a drug has activity at the G 2 /M 1 border which comprises contacting a dividing fertilized embryo with a drug and measuring or observing cleavage arrest in the embryo.
  • the drug is preferably applied to the embryo by injecting the drug into one cell of a
  • Xenopus blastomere which contains two cells and comparing the rate of cleavage of the injected cell with the rate of cleavage of the other cell of the blastomere.
  • the drug can be contacted with two separate cells in two separate test tubes and the rate of arrest of cleavage of the cell containing the drug under study can be compared with the rate of cleavage of the cell (control cell) which has not been contacted with the drug. If the drug causes an arrest in cleavage of the blastomere, then it is possible that this drug has activity at the G 2 /M 1 border.
  • An extract from the cleavage arrest cell can then be tested for MPF or histone kinase by the MPF assay reported by Sagata et al.. Nature, 355, 519-525 (1988) or the histone kinase assay reported by Ducommun et al., Analytical
  • the present invention is also directed to a method for evaluating the efficacy of anticancer drugs by contacting a mixture of a non-transformed parental cell line and an oncogene transformed derivative of the parental cell line with an anticancer drug or combination of anticancer. drugs.
  • a second mixture of the non- transformed parental cell line and derivative transformed by a different oncogene is contacted with the same anticancer drug or combination of drugs. The effect of the anticancer drug or drugs on the the oncogene
  • transformed cell lines is compared to the non-transformed cell line and the effect of the anticancer drug or drugs on each oncogene transformed cell line is compared.
  • a second anticancer drug or combination of drugs may be contacted with the same mixtures described above for comparison of different anticancer drugs on the same oncogene transformed cell lines. This method may also be used for predicting which human cancers are sensitive to an anticancer drug.
  • Fig. 1 Cellular localization of oncogene, proto- oncogene, and tumor suppressor gene products. Depicted are certain members of each oncogene family: growth factors (external mitogenic signals) (a); transmembrane tyrosine kinase growth factor receptors (b); nonintegral membrane-associated proteins of the src gene family (c) and ras gene family (d); and oncogene products localized in the nucleus (e). Fi ⁇ . 2. Expression patterns of c-mos RNA and Mos protein (pp39 mos ) during early development of Xenopus laevis (Sagata et al., Nature. 342, 512-518 (1989)).
  • C-mos RNA is represented by dots and Mos protein by the hatched area.
  • the developmental stages for oogenesis and embryogenesis are indicated.
  • F fertilization
  • FE fertilized egg
  • G gastrulation
  • GVBD germinal vesicle breakdown
  • H hatching
  • LB lampbrush stage
  • MBT mid-blastula transition
  • UFE unfertilized egg
  • V start of vitellogenesis
  • PG progesterone (Watanabe et al.,
  • NIH/3T3 cells transformed by c-mos xe were labeled for 17 hours with [ 35 S]cysteine at a concentration of 0.5 mCi/ml in cysteine-free medium.
  • the cytosol extract was
  • histogram bar represent the number of embryos arrested in cleavage over the number of embryos injected.
  • Crude MPF extracts were prepared (Lohka et al., J. Cell Biol., 101, 518-523 (1985)) from groups of ten embryos 5 to 6 hours after they had been injected with the indicated solutions as described in Table 1. These extracts were tested for MPF activity (Lohka et al., J. Cell Biol., 101, 518-523 (1985)).
  • Bottom panel Comparison of growth curves of transformed and non-transformed fibroblasts at 3 different taxol concentrations (0, 0.25, and 0.5 ⁇ M taxol). Squares - mos-transformed; diamonds - non- transformed 3T3 fibroblasts.
  • Bottom panel Growth curves of 3T3 fibroblasts at five different cis-platinum
  • FIG. 12. Top Panel: Growth curves of ras
  • taxol 5.0 ⁇ M (upside down triangles).
  • Drug - any active agent which has a biological effect on cell growth or cell cycle including, but not limited to, traditional anticancer drugs such as those shown in Table 4, proteins having anticancer activity such as tumor necrosis factor and lymphotoxin, and
  • S-phase drug - a drug which exerts its primary cytostatic or cytotoxic effect on mammalian cell cycle prior to or during S-phase.
  • M-phase drug - a drug which exerts its primary cytostatic or cytotoxic effect on mammalian cell cycle after S-phase but prior to or during M-phase.
  • Oncogene - altered form or expression of a proto-oncogene which leads to a transformed phenotype in a cell and/or tumor formation is a proto-oncogene - altered form or expression of a proto-oncogene which leads to a transformed phenotype in a cell and/or tumor formation.
  • Proto-oncogene - a gene which regulates normal cell function.
  • Transformed phenotype - a phenotype which is not characteristic of a normal (non-cancerous) cell which includes loss of contact inhibition, altered morphology and loss of genetic stability.
  • Metaphase the stage of mitosis or meiosis when chromosomes are aligned along the equatorial plane of the spindle.
  • Interphase - the state of the eukaryotic nucleus when it is not engaged in mitosis or meiosis; consists of G 1 , S, and G 2 periods in cycling cells.
  • the inventors have postulated that the expression of mos during interphase in somatic cells selects for a level of product that does not arrest at mitosis but does result in expression of a partial M-phase phenotype.
  • the altered cell morphology may equate with the cytoskeletal changes that occur normally during mitotic rounding.
  • the loss of contact inhibition is an M-phase phenotype expressed by daughter cells during cytokinesis, since daughter cell formation is not growth arrested by contact. Genetic instability of transformed cells (Table 1) could be due to premature chromatin condensation events.
  • checkpoint function which has been described in yeast (Hartwell et al., Science, 246, 629-634 (1989)). These checkpoints are pauses that occur at specific points in the cell cycle for purposes of correcting errors, such as the fidelity of replicated DNA. While mutations in the checkpoint genes could result in a high frequency of mutations that lead to malignant transformation (Hartwell et al., Science, 246, 629-634 (1989)), it is proposed that activation of an oncogene that functions downstream of the checkpoint (e.g., constitutive expression of mos product) could compromise checkpoint function anywhere upstream on the cell cycle. This provides an explanation both for the genetic instability of tumor cells and for the greater sensitivity of tumor cells to chemo-therapeutic agents compared to non-tumor cells. A number of oncogenes induce morphological
  • Taxol is a compound that influences influence of oncogenes on the cancer cell.
  • Tamoxifen (anti-estrogen) Vincristine (tubulin binding) Prednisone (corticosteriod) Vinblastine (tubulin binding) Decarbazine (DNA alkylation) Taxol (tubulin binding)
  • Cis platnium DNA cross-linking
  • Daunorubicin topoisomerase II inhibitor
  • Fig. 4 The consideration of whether they function upstream or downstream in the cell cycle may have important implications in drug therapy (Fig. 4). Specifically, the possibility for tumor cells to develop drug resistance due to activation of an alternate cell cycle pathway should be less if the drug target is downstream in the cell cycle.
  • drugs like DNA alkylating agents may preferentially target tumor cells over normal cells if the cell cycle checkpoint function (Hartwell et al., Science, 246, 629-634 (1989)) in tumor cells has been compromised. For example, repair of DNA alkylation would be compromised and alternations in mitotic apparatus would go unchecked.
  • the vulnerability of tumor cells to antineoplastic drugs that target M-phase activity like tubulin-specific agents and topoisomerase II inhibitors, might differentially recognize a gain in function due to oncogene-induced M- phase activity.
  • acute non-lymphocytic leukemia, testicular cancer, and Hodgkins lymphoma are tumors that are treated with drugs from both categories.
  • preponderance of either S-phase or M-phase agents in MOPP and ABVD regimens for Hodgkins lymphoma might explain the efficacy of one drug regimen as salvage chemotherapy after the other has failed.
  • SRB growth cuxve assays may be performed by plating 3T3 mouse fibroblasts at a suitable concentration, preferably 50,000 per ml, in microtiter plates,
  • 96 well microtiter plates Falcon
  • the cells are then allowed to attach, preferably overnight, before exposure to various concentrations of chemotherapeutic agents.
  • the plates can be fixed and stained with 0.4% sulforhodamine at 24, 48, 72 and 96 hours according to published protocols (JNCI).
  • JNCI published protocols
  • multiple runs are performed to obtain data in quadruplicate.
  • the inventors have discovered that the growth of oncogene-transformed cells may be completely inhibited by the combination of a drug having S-phase actvity and a subtherapeutic effect of a drug having M-phase activity.
  • SRB growth curve assays indicate that cis-platinum in combination with a subtherapeutic amount of taxol completely inhibits the growth of X-mos
  • the inventors have tried to explain interactions between cell cycle, oncogenes and antineoplastic drugs.
  • the studies we discuss suggest a direct link between oncogene, cell cycle activity, and antineoplastic drugs.
  • the vulnerability of certain cancers to the empirically established chemotherapeutic protocols may be related to the oncogene activated and its influence on the cell cycle.
  • chemotherapeutic agents than the parental cell line.
  • mos proto-oncogene product is an essential component of cytostatic factor (CSF), which has been shown to directly or
  • mos proto-oncogene product functions during M-phase (Sagata et al., Nature, 342, 512-518 (1989); Sagata et al., Nature, 335, 519-525 (1988); Sagata et al., Science, 245, 643-646 (1989);
  • CSF an activity present in mature oocytes
  • pp39 mos is active in arresting oocytes at metaphase II of meiosis. This phase is considered to be a major cell cycle control point and is where the highest levels of MPF are found (Murray et al., Science, 246, 614-621 (1989)). CSF directly or indirectly stabilizes MPF (Sagata et al., Nature, 342, 512-518 (1989); Gerhart et al., J.
  • the mos product as an active component of CSF, provides a direct link between proto-oncogene activity and the cell cycle regulators p34 cdc2 and cyclin.
  • the inventors' recent focus has been to identify what CSF represents and to characterize the biochemical properties of the mos product.
  • the mos product is required throughout maturation in both mouse (Paules et al., Proc. Natl. Acad. Sci. USA, 86, 5395-5399 (1989); O'Keefe et al., Dev. Biol., 60,, 7038-7042 (1989)) and
  • Xenopus oocytes (Sagata et al., Nature, 335, 519-525 (1988)), and its depletion results in the arrest of the process. As mentioned above, such oocytes lack MPF
  • Microtubule-mediated cytoplasmic organelle transport is interrupted following GVBD (Paules et al.,
  • mos may have a microtubule-related activity is that blastomeres arrested by CSF were shown by Meyerhof and Masui (Meyerhof et al., Dev. Biol., 80, 489-494 (1979)) to have a larger than normal mitotic spindle.
  • taxol a microtubule- stabilizing and tubulin-polymerizing antineoplastic drug (Schiff et al., Proc. Natl. Acad. Sci. USA, 77, 1561-1565 (1980); Schiff et al., Nature, 277, 665-667 (1979)), mimics CSF/mos in blastomeres (Heidemann et al., Dev.
  • mos product immunoprecipitated from transformed cells metabolically labeled with methionine shows a band with the mobility of tubulin (Fig. 3).
  • An equivalent precipitate, eluted and reprecipitated with tubulin antibodies shows that both ⁇ -and ⁇ -tubulin are present.
  • the same analyses performed on unlabeled extracts from either transformed cells or from unfertilized Xenopus eggs, and subjected in vitro to phosphorylation by mos kinase, show that both pp39 mos and tubulin are phosphorylated (Fig. 3).
  • mos product in unfertilized eggs By immunofluorescence analysis the mos product in transformed cells also colocalizes with tubulin at the metaphase spindle pole. In early telophase, mos protein colocalizes with tubulin in the mid-body and aster that becomes the new microtubule-organizing center of the daughter cells.
  • the mos product may function to modify microtubules and contribute to the formation of the spindle.
  • the appearance of the mos product during meiosis coincides with both formation of the spindle and stabilization of MPF at metaphase II of meiosis (Sagata et al., Science, 245, 643-646 (1989); Watanabe et al., Nature, 342, 505- 511 (1989)).
  • mos proteolysis occurs concomitantly with poleward migration of chromosomes at anaphase.
  • pp39 mos contribution to the spindle results in metaphase arrest, and its loss is associated with chromosome migration.
  • An interesting possibility is that during interphase, a limited
  • modification of microtubules by mos product may be responsible for the transformed phenotype.
  • pp3g mos with microtubules provides a vehicle to direct the kinase to specific substrates. This would allow B2 cyclin to be a potential substrate for pp39 mos (Roy et al., Cell, 61, 825-831 (1990)). Although, in mos-transformed cells, MPF is not present during G 1 and S-phases
  • M-phase promoting factor M-phase promoting factor
  • GVBD germinal vesicle breakdown
  • MPF is comprised of the Xenopus homolog of the cell cycle regulator p34 cdc2 and cyclin (J. Gautier et al., Cell, 54, 433 (1988); W.G. Dunphy et al., Cell, 54, 423 (1988); J. Gautier et al., Cell, 60, 487 (1990)), and is present at high levels in
  • Cytostatic factor is also found in unfertilized eggs and is believed to be responsible for the arrest of maturation at metaphase II of meiosis (Y. Masui et al., Int. Rev. Cvtol., 57, 185 (1979); J.W.
  • the mos proto-oncogene product has been shown to be an active component of CSF, and introduction of CSF or mos into blastomeres of rapidly cleaving embryos arrests cleavage at metaphase of mitosis (Y. Masui et al., Int. Rev. Cvtol., 57, 185 (1979); J.W. Newport et al., Cell, 37, 731 (1984); N.
  • the ras oncoprotein, p21, and the mos proto-oncogene product, pp39 mos induce progesterone-independent meiotic maturation in Xenopus oocytes (N. Sagata et al., Science, 245 643 (1989); C. Birchmeier et al., Cell, 43, 615
  • H-ras val12 RNA oncoprotein or H-ras val12 RNA. Injected oocytes were subsequently examined for GVBD and MPF activity. Cloned Xenopus mos was inserted into the Sac I restriction site of a modified pTZ18 vector having a polyA tail. The H-ras val12 cDNA was ligated into the Sal I and Bam HI
  • RNAs were capped and transcribed by the method recommended by the supplier (Stratagene) using either T7 or SP6 RNA polymerase.
  • ras lys12 p21 proteins were purified as described in Hayag et al., Oncogene, 5,, 1481 (1990).
  • Crude MPF extracts were prepared as previously described in Sagata et al., Science, 245, 643 (1989). Briefly, groups of 10 to 20 oocytes were homogenized in 20 to 40 ⁇ l of MPF extract buffer [80 mM sodium ⁇ -glycerophosphate
  • ⁇ - B buffer
  • S sense
  • AS antisence
  • Xenopus laevis females were obtained from Xenopus I (Ann Arbor, MI). Oocytes were removed from the surrounding follicle tissue by the addition of modified Barth solution (MBS) containing collagenase A (2 mg/ml; Boehringer Mannheim) (Durkin et al., Mol. Cell. Biol., 7, 444 (1987)) and incubated for 2 hours. The oocytes were washed extensively with MBS, and stage VI (Dunmont, J. Morphol., 136, 153 (1972)) oocytes were removed and allowed to recover overnight.
  • MBS modified Barth solution
  • stage VI Unmont, J. Morphol., 136, 153 (1972)
  • oocytes Groups of 10 to 30 oocytes were microinjected using an Attocyte injector (ATTO Instruments) with 40 nl of the appropriate reagent diluted to the desired concentration in 88 mM NaCl and 15 mM Tris (pH 7.5).
  • Attocyte injector ATRO Instruments
  • oocytes were cultured for 3.5 to 4 hours before the second indicated treatment or injection.
  • GVBD was determined 14 to 18 hours later by the
  • oligodeoxyribonucleotides destabilize the mos maternal mRNA and block progesterone-induced meiotic maturation (N. Sagata et al., Nature, 335, 519 (1988); C.B. Barrett et al., Mol. Cell. Biol., 10, 310 (1990)).
  • progesterone-induced meiotic maturation N. Sagata et al., Nature, 335, 519 (1988); C.B. Barrett et al., Mol. Cell. Biol., 10, 310 (1990)
  • the ras oncoprotein efficiently arrested embryonic cleavage when one blastomere of each 2-cell embryo was injected with either oncogenic ras p21 or RNA.
  • This cleavage arrest mimics the arrest caused by CSF or the mos product (N. Sagata et al., Nature, 342 , 512
  • ras oncogene product can induce the cleavage arrest, which is observable within a few hours.
  • ras lys12asn17 (L.A. Feig et al., Mol. Cell. Biol., 8, 3235 (1988)) was ineffective at ceasing cell division, as was ras lys ⁇ 153-164 , which is
  • oncogene-arrested embryos were assayed biologically and biochemically for MPF activity. Extracts from both mos and ras-arrested embryos exhibited high levels of MPF, as assayed in cycloheximide-treated oocytes. Moreover, extracts from embryos arrested by either the ras oncogene or authentic CSF had equally high levels of MPF- associated histone H1 kinase activity when compared to the amount detected in extracts from control-activated eggs. Thus, the ras oncoprotein can arrest cleaving embryos in mitosis, as evidenced by the presence of high levels of MPF and the associated histone H1 kinase activity.
  • the ras oncoprotein can induce meiosis or arrest embryonic cells in mitosis and therefore must directly or indirectly influence M-phase events.
  • insulin-induced meiotic maturation occurs through a pathway requiring endogenous P21 ras as well as mos function (N. Sagata et al., Nature, 335, 519 (1988); A.K. Desphande et al., Mol. Cell. Biol., 7, 1285 (1987); L.J. Korn et al.,
  • oncogenic ras in fully grown stage VI oocytes, can induce maturation through a mos- independent pathway (Table 1).
  • the high levels of MPF observed in the mature oocytes or in the ras oncoprotein-arrested blastomeres are consistent with an arrest in metaphase.
  • CSF activity induced by the mos or ras oncogenes raises the question of how embryonic cleavage arrest relates to transformation of somatic cells.
  • Cells acutely infected with Moloney murine sarcoma virus express high levels of mos product (J. Papkoff et al., Cell, 29, 417 (1982)), subsequently round up, and detach from the monolayer (P.J. Fischinger et al., J. Gen. Virol., 13, 203, (1971)). This morphological alteration is
  • Ki- ras p21 promotes G 2 /M transition in serum-free medium.
  • high levels of ras oncoprotein expression increase the rate of abnormal mitosis in NIH/3T3 cells (N. Hayag et al., Oncogene, 5, 1481 (1990)).
  • oncogene product exhibits CSF-like activity in embryos without the assistance of pp39 mos and provides additional evidence that other products possess CSF activity.
  • CSF may mediate cell cycle arrest through a feedback
  • the top left figure shows the growth of the non-transformed fibroblasts at the three taxol concentrations, which inhibit, but do not arrest growth.
  • the top right figure shows the growth of the transformed fibroblasts at the three taxol concentrations. As can be seen, the taxol completely arrests the growth of the cells.
  • the bottom three graph compare the growth of non-transformed versus transformed cells at each of the three taxol concentrations. As can be seen, the growth
  • Mouse fibroblasts (3T3) transformed by over-expression of the Xenopus-mos proto-oncogene were mixed with non-transformed 3T3 fibroblasts at three dilutions, 100:1, 1000:1 and 10,000:1.
  • the cells were plated at a concentration of 500,000 cells per 60 mm dish. The cells were allowed to grow for 24 hours before changing the media. The media was changed every third day, with the plates being scored for focus formation on day 10. The plates were incubated either with medium containing 1 micromolar taxol, or no taxol. As can be seen from
  • Figure 8 shows the growth curves of Mu-met
  • the top curve displays cell growth in the absence of cis-platinum and taxol.
  • the middle curve indicates moderate growth inhibition in the presence of 2.5 ⁇ M cis-platinum.
  • the bottom curve shows that the 2.5 ⁇ M cis-platinum.
  • the bottom curve shows that the addition 0.25 ⁇ M taxol, a subtherapeutic concentration, essentially resulted in complete inhibition of the growth of Mu-met transformed cells.
  • Figure 9 shows the growth curves of X-mos transformed cells.
  • the top curve displays cell growth in the absence of cis-platinum and taxol.
  • the middle curve indicates moderate growth inhibition in the presence of 2.5 ⁇ M cis-platinum.
  • the bottom curve shows that the addition of 0.25 ⁇ M taxol, a subtherapeutic
  • Non-transformed 3T3 mouse fibroblasts and 3T3 fibroblasts transformed by the murine and Xenopus c-mos, murine c-met and the human ras oncogene were
  • mice were evaluated at 10, 14, and 28 days for tumor
  • mice palpable tumors within seven to ten days after injection. No tumors were observed in mice injected with the
  • Mouse fibroblasts (3T3) transformed by the Xenopus mos protooncogene were mixed with non-transformed 3T3 fibroblasts at three ratios of dilution: 100:1, 1000:1 and 10,000:1.
  • the cell suspensions were plated at a concentration of 500,000 cells per 35 mm dish and were allowed to attach for 24 hours before changing the
  • Cis-platinum and methotrexate showed only a slight effect on the transformant colonies as to the inhibition of focus formation.

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Abstract

Procédé de conception de traitements du cancer basé sur l'effet de médicaments sur diverses phases du cycle de cellules mammifères telles que la phase S, la phase M, ainsi que des points de contrôle dans le cycle cellulaire. L'invention concerne également des techniques de diagnostic spécifiques pouvant être utilisées pour mesurer l'activité de médicaments anticancéreux, ainsi que des compositions pharmaceutiques anticancéreuses.
PCT/US1992/003830 1991-05-08 1992-05-08 Procede de conception de traitements du cancer, procedes et compositions pharmaceutiques de traitements du cancer WO1992019765A1 (fr)

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GB2269319A (en) * 1992-08-03 1994-02-09 Bristol Myers Squibb Co Compositions containing taxol
WO1994010995A1 (fr) * 1992-11-10 1994-05-26 Rhone-Poulenc Rorer S.A. Compositions antitumorales contenant des derives du taxane
EP0624096A1 (fr) * 1992-01-31 1994-11-17 The Trustees of Columbia University in the City of New York Taxol utilise comme sensibilisateur aux rayonnements
WO1997001344A3 (fr) * 1995-06-27 1997-03-27 Jackson H M Found Military Med Procede de ralentissement dynamique de la cinetique du cycle cellulaire, destine a potentialiser les lesions cellulaires
US5621001A (en) * 1992-08-03 1997-04-15 Bristol-Myers Squibb Company Methods for administration of taxol
US6274576B1 (en) 1995-06-27 2001-08-14 The Henry Jackson Foundation For The Advancement Of Military Medicine Method of dynamic retardation of cell cycle kinetics to potentiate cell damage
US6441026B1 (en) 1993-11-08 2002-08-27 Aventis Pharma S.A. Antitumor compositions containing taxane derivatives
US6927211B2 (en) 2000-09-22 2005-08-09 Bristol-Myers Squibb Company Method for reducing toxicity of combined chemotherapies
US7074821B1 (en) 1992-12-09 2006-07-11 Aventis Pharma, S.A. Taxoids, their preparation and pharmaceutical composition containing them

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CANCER TREATMENT REPORTS, Volume 71 (4), issued April 1987, F. BREWER et al., "Verapamil Reversal of Vincristine Resistance and Cross-Resistance Patterns of Vincristine-Resistant Chinese Hamster Ovary Cells", pages 354-359. *
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NATURE, Volume 342, issued 30 November 1989, SAGATA N. "The C-Mos Product is a Cytostatic Factor Responsible for Meiotic Arrest in Vertebrate Eggs", pages 412-518. *
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SCIENCE, Volume 251, issued 08 February 1991, R. ZHOU et al., "Ability of the C-Mos Product to Associate with and Phosphorylate Tubulin", pages 671-675. *
THE YALE JOURNAL OF BIOLOGY AND MEDICINE, Volume 64, issued March-April 1991, H. BARBER, "New Frontiers in Ovarian Cancer Diagnosis and Management", pages 127-141. *
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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0624096A1 (fr) * 1992-01-31 1994-11-17 The Trustees of Columbia University in the City of New York Taxol utilise comme sensibilisateur aux rayonnements
EP0624096A4 (fr) * 1992-01-31 1995-04-19 Univ Columbia Taxol utilise comme sensibilisateur aux rayonnements.
US5621001A (en) * 1992-08-03 1997-04-15 Bristol-Myers Squibb Company Methods for administration of taxol
GB2269319A (en) * 1992-08-03 1994-02-09 Bristol Myers Squibb Co Compositions containing taxol
US5665761A (en) * 1992-08-03 1997-09-09 Bristol-Myers Squibb Company Methods for administration of taxol
GB2269319B (en) * 1992-08-03 1997-04-09 Bristol Myers Squibb Co Methods for administration of taxol
US5908835A (en) * 1992-11-10 1999-06-01 Rhone-Poulenc Rorer, S.A. Anti-tumor compositions containing taxane derivatives
EP0827745A1 (fr) * 1992-11-10 1998-03-11 Aventis Pharma S.A. Compositions antitumorales contenant des derives du taxane
US5728687A (en) * 1992-11-10 1998-03-17 Rhone-Poulenc Rorer, S.A. Antitumour compositions containing taxane derivatives
WO1994010995A1 (fr) * 1992-11-10 1994-05-26 Rhone-Poulenc Rorer S.A. Compositions antitumorales contenant des derives du taxane
EP1093811A1 (fr) * 1992-11-10 2001-04-25 Aventis Pharma S.A. Compositions antitumorales contenant des dérivés du taxane
US8124650B2 (en) 1992-11-10 2012-02-28 Aventis Pharma S.A. Antitumor combinations containing taxane derivatives and epidophyllotoxins
US8101652B2 (en) 1992-11-10 2012-01-24 Aventis Pharma S.A. Antitumour combinations containing taxotere and 5-fluorouracil
US7994212B2 (en) 1992-11-10 2011-08-09 Aventis Pharma S.A. Method of treating cancer with docetaxel and doxorubicin
EP1295597A1 (fr) * 1992-11-10 2003-03-26 Aventis Pharma S.A. Compositions antitumorales contentant des derives du taxane
US7989489B2 (en) 1992-11-10 2011-08-02 Aventis Pharma S.A. Method of treating leukemia with docetaxel and vinca alkaloids
US7074821B1 (en) 1992-12-09 2006-07-11 Aventis Pharma, S.A. Taxoids, their preparation and pharmaceutical composition containing them
US6441026B1 (en) 1993-11-08 2002-08-27 Aventis Pharma S.A. Antitumor compositions containing taxane derivatives
US6455593B1 (en) 1995-06-27 2002-09-24 The Henry Jackson Foundation For The Advancement Of Military Medicine Method of dynamic retardation of cell cycle kinetics to potentiate cell damage
WO1997001344A3 (fr) * 1995-06-27 1997-03-27 Jackson H M Found Military Med Procede de ralentissement dynamique de la cinetique du cycle cellulaire, destine a potentialiser les lesions cellulaires
US6274576B1 (en) 1995-06-27 2001-08-14 The Henry Jackson Foundation For The Advancement Of Military Medicine Method of dynamic retardation of cell cycle kinetics to potentiate cell damage
US6927211B2 (en) 2000-09-22 2005-08-09 Bristol-Myers Squibb Company Method for reducing toxicity of combined chemotherapies

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