US20040180955A1 - Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy - Google Patents

Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy Download PDF

Info

Publication number
US20040180955A1
US20040180955A1 US10/807,620 US80762004A US2004180955A1 US 20040180955 A1 US20040180955 A1 US 20040180955A1 US 80762004 A US80762004 A US 80762004A US 2004180955 A1 US2004180955 A1 US 2004180955A1
Authority
US
United States
Prior art keywords
suramin
dose
patient
bsa
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/807,620
Other languages
English (en)
Inventor
Jessie Au
M. Wientjes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US10/807,620 priority Critical patent/US20040180955A1/en
Publication of US20040180955A1 publication Critical patent/US20040180955A1/en
Priority to US13/031,306 priority patent/US8580857B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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 a method to determine the dose requirements of suramin used as a chemosensitizer to enhance the efficacy of other chemotherapeutic agents.
  • Suramin is an anticancer agent with modest activity in single agent therapy.
  • a large number of previous studies have evaluated suramin in high-dose regimens, either as single agent or in combination with other chemotherapeutics. These studies, which aimed to achieve plasma concentrations between 150 and 300 ⁇ g/ml or about 100 to 200 ⁇ M, showed a modest activity of high-dose suramin for single agent therapy, in the face of extensive drug toxicity. (Eisenberger, et al (1995) J Clin Oncol 13:2174-2186).
  • a typical suramin dosing schedule aimed at maintaining suramin plasma concentrations between 100 and 200 ⁇ g/ml consists of an initial administration of 2100 mg/m 2 in the first week with the subsequent doses repeated every 28 days for 6 months or longer; the subsequent doses are adjusted using the Bayesian pharmacokinetic method (Dawson, et al (1998) Clin Cancer Res 4:37-44, Falcone, et al (1999) Cancer 86:470-476).
  • the methods of the art for using suramin in combination with other cytotoxic agents often administer high doses of suramin at a more frequent schedule or a longer duration compared to the frequency and the treatment duration for the other cytotoxic agents.
  • the duration of doxorubicin treatment was up to 20 weeks, whereas the duration of the suramin treatment was up to 45 weeks (Tu, et al (1998) Clin Cancer Res 4:1193-1201).
  • suramin was given weekly whereas mitomycin C was given only every 5 weeks (Rapoport, et al (1993) Ann Oncol 4:567-573).
  • suramin causes the following toxicity in a human patient: adrenal insufficiency, coagulopathy, peripheral neuropathy, and proximal muscle weakness (Dorr and Von Hoff, Cancer Chemotherapy Handbook, 1994, pp 859-866).
  • adrenolytic toxicity patients on high-dose suramin regimens were co-administered replacement steroid treatments (Dorr and Von Hoff, id).
  • Applicants have disclosed in a previous patent application (PCT/US00/40103) that acidic and basic fibroblast growth factors (aFGF and bFGF) present in tumor tissues induce resistance of tumor cells to chemotherapy, and that this FGF-mediated resistance can be overcome by low concentrations of suramin of less than about 50 ⁇ M.
  • aFGF and bFGF acidic and basic fibroblast growth factors
  • the present invention shows that only low doses of suramin, which yielded between about 10 to about 50 ⁇ M plasma concentrations over the duration (e.g., 6 hours) when a chemotherapeutic agent (e.g., paclitaxel) was present in the plasma at therapeutically significant levels, enhanced the efficacy of chemotherapy in tumor-bearing animals.
  • a chemotherapeutic agent e.g., paclitaxel
  • high doses of suramin that yielded concentrations between about 300 to about 650 ⁇ M over about the same duration, did not enhance the efficacy and only enhanced the toxicity of chemotherapy.
  • Applicants disclose the results of a Phase I trial, showing that addition of low dose suramin, that yielded between about 10 to about 50 ⁇ M plasma concentrations, over the duration when other chemotherapeutic agents (i.e., paclitaxel and carboplatin) were present at therapeutically significant levels, enhanced the response of cancer patients to a standard therapy of paclitaxel plus carboplatin.
  • chemotherapeutic agents i.e., paclitaxel and carboplatin
  • the invention discloses a 180% inter-subject variability in suramin disposition in cancer patients, in part due to slower drug elimination in female patients compared to male patients. This gender-related difference in suramin elimination has not been previously demonstrated.
  • the large inter-subject variability indicates that administering the same dose of suramin will not result in the same, desired plasma concentrations in all patients.
  • the invention discloses a simple and practical method to calculate a suramin dose in individual patients, based on the target chemosensitizing suramin concentrations and duration of suramin exposure (e.g., plasma concentrations of between about 10 to about 50 ⁇ M maintained over 48 hours), and demographic characteristics of a patient including, but not limited to, the squared value of the body surface area and gender of a patient, and the duration between treatments.
  • This new method therefore, can be used to calculate the suramin dose for use as a chemosensitizer, in both male and female patients, and can accommodate delay in treatments.
  • the invention is based, at least in part, on the following discoveries by the inventors.
  • the chemosensitizing effect of suramin is highly dose-dependent and concentration-dependent, and occurs at a concentration range of between about 10 to about 50 ⁇ M and below about 300 to about 650 ⁇ M maintained over the duration when the co-administered chemotherapeutic agent is present at therapeutically significant levels.
  • Applicants also tested in cancer patients the use of low doses of suramin selected to deliver plasma concentrations in the range known to produce chemosensitization in tumor-bearing animals, over the duration when other chemotherapeutic agents (i.e., paclitaxel and carboplatin) were present in the plasma at therapeutically significant levels (e.g., about 10 to about 50 ⁇ M suramin concentrations over 48 hours).
  • chemotherapeutic agents i.e., paclitaxel and carboplatin
  • Applicants further found that the elimination of suramin, at the low dose that yielded between about 10 to about 50 ⁇ M over 48 hours produces chemosensitization, is more rapid and shows more inter-subject variability in human cancer patients, compared to the results shown in the prior art when suramin was given at high doses that yielded between about 100 to about 200 ⁇ M plasma concentrations in patients.
  • the invention discloses a method for calculating, for individual patients, the suramin dose that would yield the desired plasma suramin concentrations known to produce chemosensitization.
  • the invention further discloses a method to prepare nomograms and discloses nomograms for calculating the suramin dose in individual patients.
  • FIG. 1 graphically depicts the effect of suramin dose on chemosensitization.
  • Immunodeficient mice bearing well-established subcutaneous human prostate PC3 xenograft tumors were treated with saline (controls), a chemotherapeutic agent (i.e., paclitaxel), low dose suramin, high dose suramin, a combination of paclitaxel plus low dose suramin, or a combination of paclitaxel plus high dose suramin.
  • the dose of paclitaxel was 15 mg/kg and was given twice weekly for three weeks. Two doses of suramin were used.
  • the low suramin dose was 10 mg/kg and was given twice weekly for three weeks.
  • the high suramin dose group received a loading dose of 200 mg/kg, followed by 5 doses of 130 mg/kg each, over three weeks.
  • Example 1 further expounds on FIG. 1.
  • cytotoxic agent As used herein, the terms “cytotoxic agent”, “chemotherapeutic agent”, “anticancer agent”, and “antitumor agent” are used interchangeably herein and refer to agents that have the property of inhibiting the growth or proliferation (e.g., a cytostatic agent), or inducing the killing, of hyperproliferative cells.
  • a “therapeutically effective amount” of suramin refers to an amount of suramin that is effective, upon single- or multiple-dose administration to the subject, e.g., a patient, at inhibiting the growth or proliferation, or inducing the killing, of hyperproliferative cells, e.g., cancer cells.
  • terapéuticaally effective amount also refers to an amount of suramin that is administered, e.g., coadministered, (i.e., sequentially or concomitantly) with one or more cytotoxic agents such that suramin and the cytotoxic agent, are effective, upon single- or multiple-dose administration to the subject, e.g., a patient, at inhibiting the growth or proliferation, or inducing the killing, of hyperproliferative cells.
  • Such growth inhibition or killing can be reflected as a prolongation of the survival of the subject, e.g., a patient beyond that expected in the absence of such treatment, or any improvement in the prognosis of the subject relative to the absence of such treatment.
  • chemosensitization and “chemosensitizing effect” are used interchangeably and refer to the enhancement of chemotherapy efficacy by suramin.
  • Cosmeticizer refers to the agent, e.g., suramin, that enhances the efficacy of another agent.
  • high dose suramin and “high dose(s) of suramin” are used interchangeably and refer to suramin used as a cytotoxic agent and at doses that when injected into a subject, result in a plasma concentration range of between about 300 to about 650 ⁇ M maintained for about six to eight hours, or result in a plasma concentration range of between 100 to 200 ⁇ M maintained for more than one or two months.
  • low dose suramin refers to suramin used as a chemosensitizer and at doses that when injected into a subject, result in a plasma concentration range of below about 300 to about 650 ⁇ M maintained for about six to eight hours, or result in a plasma concentration range of between 100 to 200 ⁇ M maintained for more than one or two months.
  • high dose suramin regimen refers to a treatment that administers a high dose of suramin to a subject.
  • low dose suramin regimen refers to a treatment that administers a low dose of suramin to a subject.
  • “duration when the co-administered chemotherapeutic agent(s) are present at therapeutically significant concentrations or levels” refers to the time period when the co-administered chemotherapeutic agent is present or detectable in the circulating blood or plasma, or the duration over which the exposure to the co-administered chemotherapeutic agent accounts for about 90% of the total exposure to the co-administered agent, e.g., measured as area-under-concentration-time-curve, or the duration which is approximately equal to three to four terminal half-lives of the co-administered chemotherapeutic agent.
  • cognates refers to physiological or pathological parameters of patients that may contribute to the inter-subject variability in the elimination of low dose suramin.
  • PBPK refers to population-based pharmacokinetic analysis
  • PBPK-based dosing method refers to a method developed using PBPK to determine the suramin dosing regimens that produce chemosensitization. This method is detailed in EXAMPLE IV.
  • a nomogram refers to a tabulation and/or predictive formula(ae) which allow for the determination of a therapeutically effective amount(s) of an agent for administering to a subject, e.g., a human patient, based on one or more readily obtained parameters, including, but not limited to, the patient's gender, age, body weight or body surface area, or the time lapsed since the previous drug treatment.
  • the invention features the use of low dose suramin as a chemosensitizer, in combination with at least one other chemotherapeutic agent.
  • low dose suramin is administered, in combination with at least one other chemotherapeutic agent, to a subject.
  • low dose suramin is co-administered with the same, or a different chemotherapeutic agent, to a subject.
  • low dose suramin is co-administered with repeated dosages of the same, or a different chemotherapeutic agent, to a subject.
  • the dosing schedule of low dose suramin yields plasma concentrations of suramin, preferably below the range of between about 300 to about 600 ⁇ M, preferably below the range of between about 150 to about 200 ⁇ M, advantageously below the range of between about 135 to about 200 ⁇ M, more advantageously below the range of between about 120 to about 200 ⁇ M, preferably below the range of between about 105 to about 200 ⁇ M, more preferably below the range of between about 90 to about 200 ⁇ M, more preferably below the range of between about 75 to about 200 ⁇ M, more preferably below the range of between about 60 to about 200 ⁇ M, and even more preferably at the range of between about 10 to about 50 ⁇ M, over the duration when a co-administered chemotherapeutic agent is present in the subject at therapeutically significant levels.
  • a chemotherapeutic agent is given repeatedly for multiple treatment cycles scheduled at time intervals of approximately three weeks.
  • a chemotherapeutic agent is given repeatedly for multiple treatment cycles scheduled at time intervals of approximately one week.
  • the dosing regimens of chemotherapy include administration of multiple treatment cycles administered at irregular time intervals.
  • low dose suramin is given repeatedly for multiple treatment cycles scheduled at time intervals of approximately three weeks.
  • low dose suramin is given repeatedly for multiple treatment cycles scheduled at time intervals of approximately one week.
  • the dosing regimen of low dose suramin includes administration of multiple treatment cycles scheduled at irregular time intervals.
  • the dosing regimen of low dose suramin includes repeated dosages of suramin within a single treatment cycle.
  • combination therapy of low dose suramin and at least one other chemotherapeutic agent inhibits the proliferation of, or enhances the killing of, a hyperproliferative cell derived from malignant or benign tumors, or from a benign hyperplastic growth.
  • low dose suramin is administered in combination therapy with at least one other chemotherapeutic agent to human patients.
  • low dose suramin is administered in combination therapy with at least one other chemotherapeutic agent to non-human mammals.
  • low dose suramin enhances the efficacy of the chemotherapeutic agent, e.g., a cytotoxic agent, relative to the effect of the cytotoxic agent in the absence of low dose suramin.
  • chemotherapeutic agent e.g., a cytotoxic agent
  • low dose suramin is administered with at least one chemotherapeutic agent, so as to inhibit the proliferation of, or to enhance the killing of, a hyperproliferative cell derived from malignant or benign tumors.
  • suramin is administered with at least one cytotoxic agent.
  • the enhanced, and sometimes synergistic, effect of suramin with at least one anticancer agent in addition to improving the efficacy of these anticancer agents, may allow for the administration of lower doses of these anticancer agents, thus reducing the induction of side effects in a subject, (e.g., a patient).
  • the subject is a patient with non-small cell lung cancer, who is treated with a combination of paclitaxel, carboplatin, and suramin.
  • the invention teaches not to use high dose suramin, in combination with other chemotherapeutic agents.
  • high doses of suramin i.e., above about 200 to 300 ⁇ M
  • administration of a chemotherapeutic agent is delayed until the plasma concentrations of suramin have decreased to between the range of about 10 to 50 ⁇ M, during which time the chemotherapeutic agent is administered.
  • the invention features a method of identifying the dose of suramin to be used as a chemosensitizer, in combination with an agent, e.g., a cytotoxic agent, in a subject.
  • the method is comprised of the steps of:
  • the invention features a method for determining, for a chemotherapeutic agent, the extent of enhancement of therapeutic efficacy that is obtained by chemosensitization with low dose suramin, in order to identify the chemotherapeutic agent that, when co-administered with low dose suramin to a subject, will produce the desired enhanced efficacy by suramin.
  • the invention features a method for determining a therapeutically effective amount of suramin as a chemosensitizer for administering to a patient.
  • the method is comprised of the steps of:
  • the invention features a method to derive the equations and to obtain the values of population-average pharmacokinetic parameters of low dose suramin. These equation and parameters are used for determining a therapeutically effective amount of low dose suramin used as a chemosensitizer for administering to a patient.
  • the method is detailed in Example IV and is comprised of the steps of:
  • Exemplary tumors are as described in an earlier patent application No. PCT/US00/40103. Examples of diagnosis of an established tumor also are as described in the earlier application PCT/US00/40103.
  • Exemplary benign hyperplastic growths are as described in the earlier application PCT/US00/40103.
  • suramin is administered in combination with at least one cytotoxic agent.
  • the term “in combination” in this context means that the agents are given substantially contemporaneously, either simultaneously or sequentially. If given sequentially, at the onset of administration of the second compound, the first of the two compounds is preferably still detectable at effective concentrations at the site where treatment effect is desired.
  • low dose suramin can be used in combination therapy with conventional cancer chemotherapeutics.
  • Conventional treatment regimens for tumors include radiation, antitumor agents, interferons, interleukins, tumor necrosis factors, or a combination of two or more of these agents.
  • the cytotoxic agents include, but are not limited to, an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and/or radiation.
  • a signal transduction pathway e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors
  • an agent that promotes apoptosis and/or necrosis e.g., an anti-hormone, e.g., an antibody
  • Exemplary cytotoxic agents include, but are not limited to, paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, docetaxel, topotecan, camptothecin, irinotecan hydrochloride, doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytosine arabinoside, trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2′-deoxycytidine, adenosine arab
  • Examples of additional agents that can be used in combination with low dose suramin include, but are not limited to, hydroxyurea, azathioprine, aminopterin, trimethoprin, pyrimethamine, pyritrexim, DDMP (2,4 diamino-5(3′,4′ dichlorophenyl)6 methylpyrimidine), 5,10-dideazatetrahydrofolate, 10-propargyl-5,8 dideazafolate (CB3717), 10-ethyl-10-deaza-aminopterin, deoxycytidine, 5-aza-cytosine arabinoside, N-4-palmitoyl-ara C, 2′-azido-2′-deoxy-ara C, N4-behenoyl-ara C, CCNU (lomustine), estramustine, MeCCNU, triethylene melamine, trenimon, dimethyl busulfan, streptozotocin, chlorozotocin, procarbazine, he
  • This example describes the importance of administering therapeutically effective amounts of suramin as a chemosensitizer for, e.g., enhancing chemotherapy efficacy.
  • the relevant tumor model used was human prostate PC3 xenograft implanted subcutaneously in immunodeficient mice. Drug treatment was initiated after tumors were palpable and greater than 3 mm in diameter.
  • the dose of paclitaxel was 15 mg/kg and was given twice weekly for three weeks. Two doses of suramin were used.
  • the low suramin dose was 10 mg/kg and was given twice weekly for three weeks (referred to as low dose suramin regimen).
  • Animals in the high suramin dose group received a loading dose of 200 mg/kg, followed by 5 doses of 130 mg/kg each, over three weeks (referred to as high dose suramin regimen).
  • the tumor size increased with time, reaching the highest levels of about 800% of the initial tumor size.
  • the high dose suramin group showed a slower tumor growth, indicating that high dose suramin produced antitumor activity.
  • the difference in the tumor size between the high dose suramin group and the control group was not significant (p>0.05).
  • Paclitaxel alone suppressed tumor growth; the difference in the tumor size between this group and the control group was significant (p ⁇ 0.05).
  • the combination of paclitaxel and high dose suramin showed similar effect as paclitaxel alone.
  • the combination of paclitaxel and low dose suramin showed significantly enhanced antitumor effect compared to paclitaxel alone (p ⁇ 0.05).
  • a post-treatment residual tumor consisted of apoptotic and non-apoptotic cells
  • the effects of different treatments on the fractions of non-apoptotic (and therefore not committed to death) and apoptotic (dead or committed) cells were evaluated. Briefly, residual tumors were removed from animals after termination of treatment, and histologic tumor sections were prepared. Tumor sections were examined microscopically under 400 ⁇ magnification. For each tumor, at least 4 sections were evaluated. Apoptotic cells were identified by their characteristic morphologies, i.e., presence of apoptotic bodies, condensed nuclei and fragmented nuclei. The results are shown in Table 1.
  • the control group showed the highest number of residual tumor cells and the highest number of non-apoptotic cells, per 400 ⁇ field.
  • the low dose suramin group showed a slightly lower number of non-apoptotic cells, but the difference between this group and the control was not significant (p>0.05).
  • the high dose suramin group, and the paclitaxel group the two combination groups showed significantly lower numbers of non-apoptotic cells (p ⁇ 0.05 for all four groups).
  • a comparison of the paclitaxel group and the paclitaxel/high dose suramin combination group shows similar numbers of non-apoptotic and apoptotic cells in the two groups (p>0.05), indicating that the addition of high dose suramin did not significantly alter the antitumor activity of paclitaxel.
  • the paclitaxel/low dose suramin combination group showed 7-fold fewer non-apoptotic cells compared to the paclitaxel group, indicating that the addition of low dose significantly enhanced the antitumor activity of paclitaxel (p ⁇ 0.05).
  • a Phase I trial was performed in advanced non-small lung cancer patients.
  • One of the objectives was to determine whether low dose suramin is effective in enhancing the efficacy of chemotherapy.
  • Suramin at doses that delivered plasma concentrations of between about 10 to about 50 ⁇ M for 48 hours was administered with a standard therapy, i.e., paclitaxel (200 mg/m 2 ) and carboplatin (AUC 6), every three weeks.
  • paclitaxel 200 mg/m 2
  • AUC 6 carboplatin
  • Table 2 compares the results in patients who received low dose suramin plus paclitaxel and carboplatin to the historical results in patients with comparable diseases and who received only paclitaxel and carboplatin (Laohavinij, et al. Lung Cancer, 26:175-185, 1999; Helsing, et al., Lung Cancer, 24:107-113, 1999; Langer, et al. Eur. J. Cancer, 36:183-193, 2000; Evans, et al. Lung Cancer, 18:83-94, 1997; Langer et al. J. Clin. Oncol., 13:1860-1870,1995).
  • One of the objectives of the phase I trial described in Example II was to identify the suramin dose yielding target plasma concentrations of between about 10 to about 50 ⁇ M over the duration when the chemotherapeutic agents, i.e., paclitaxel and carboplatin, were present at therapeutically significant levels in the plasma.
  • chemotherapeutic agents i.e., paclitaxel and carboplatin
  • results in the first six patients showed that nearly all of the areas-under-plasma concentration-time curves of paclitaxel and carboplatin were attained in the first 48 hours after drug administration (i.e., >92% for paclitaxel and >99% for carboplatin).
  • the target suramin concentrations were between about 10 to about 50 ⁇ M over 48 hours following the initiation of suramin infusion. These concentrations were achieved by giving the total suramin dose in two split doses, with two-thirds of the dose given on the first day and the remaining one-third given 24 hours later.
  • This schedule was found to yield the target concentration range of less than 50 ⁇ M suramin concentrations immediately after the administration of a chemotherapeutic agent, i.e., paclitaxel, and greater than 10 ⁇ M suramin concentrations at 48 hours after the initiation of suramin infusion.
  • a chemotherapeutic agent i.e., paclitaxel
  • Table 3 compares the pharmacokinetic parameters of the low dose suramin regimen used in the present study with the literature values obtained using a >8-fold higher total suramin dose (Jodrell Example et al, J Clin Oncol 12:166-75, 1994). The comparison shows three unexpected findings. First, low dose suramin shows a much faster elimination compared to high dose suramin, as indicated by the higher clearance and shorter terminal half-life of the low dose. Second, low dose suramin shows a significantly lower steady state volume of distribution compared to high dose suramin. Third, suramin is eliminated more slowly in female patients compared to male patients. These findings are surprising because the elimination of suramin was not known to be dose-dependent or gender-dependent.
  • Example I the ability of suramin to improve the chemotherapy efficacy in tumor-bearing animals is highly dependent on the suramin concentration. This is further supported by the surprising finding that low dose suramin enhanced the efficacy of chemotherapy in human lung cancer patients, as shown in Example II.
  • Example III The surprising findings of dose- and gender-dependent elimination of suramin, shown in Example III, highlight the importance to determine the dose of suramin that would yield plasma concentrations that are known to produce chemosensitization. Similarly, it is necessary to identify the high doses of suramin that do not produce chemosensitization but only potentiate the toxicity of other chemotherapeutic agents.
  • the objective of this example is to demonstrate the development of a method to identify the sources of the inter-subject variability in the suramin pharmacokinetics in patients and to use this information to identify, for individual patients, the dose of suramin that would produce chemosensitization.
  • PBPK population-based pharmacokinetic analysis
  • Table 4 summarizes the suramin pharmacokinetic parameters of the first 12 patients.
  • the clearance (CL) of suramin showed relative low inter-individual variability within each gender, with 13% variability in males and 2% variability in females. However, the CL was lower in females compared to males. This, in turn, resulted in a maximum inter-individual variability of 182%.
  • the maximum inter-subject variability in the steady state volume of distribution (Vss) was 153%.
  • PBPK analysis is used to identify the sources of inter-individual variability in pharmacokinetic parameters and is performed in a stepwise manner (Sheiner, et al., J. Pharmacokinet. Biopharm., 5: 445, 1977; Mandema, et al, J. Pharmacokinet. Biopharm., 20: 511, 1992).
  • the first step is to define the appropriate error model for the pharmacokinetic parameters of interest.
  • the physiological or pathological parameters of patients referred to as covariates
  • the Full Model the physiological or pathological parameters of patients that significantly reduce the deviation of the values in individual patients from the population mean values are incorporated into the model (referred to as the Full Model).
  • PBPK for a one-compartment model depicting plasma concentrations as a function of clearance (CL) and volume of distribution (V) is as follows:
  • C ij is the predicted plasma concentration at a particular time time i for a patient j.
  • Equations 2 and 3 describe the deviation of CL (CL j ) and V (V j ) in an individual patient from the population or typical values (CL ⁇ circumflex over ( ) ⁇ typ and V ⁇ circumflex over ( ) ⁇ typ ).
  • V j V ⁇ circumflex over ( ) ⁇ typ *(1+ ⁇ V ) Eq. 3
  • ⁇ CL and ⁇ V are random values normally distributed around a mean of zero with a variance of ⁇ 2 .
  • Equation 5 shows the relationship between CL ⁇ circumflex over ( ) ⁇ typ (the mean value of population clearance) and creatinine clearance
  • Equation 6 shows the relationship between V ⁇ circumflex over ( ) ⁇ typ (the mean value of population volume of distribution) and BSA. Similar equations were established for other covariates.
  • V ⁇ circumflex over ( ) ⁇ typ ⁇ 3 + ⁇ 4 *BSA Eq. 6
  • V ⁇ circumflex over ( ) ⁇ typ ⁇ 5 *BSA 2 + ⁇ 6 Eq. 8
  • ⁇ 1 , ⁇ 2 , and ⁇ 4 described the effects of BSA, CrCL, and gender on CL ⁇ circumflex over ( ) ⁇ typ , respectively.
  • ⁇ 4 was set to zero.
  • ⁇ 5 is the proportionality constant that described the effect of (BSA 2 ) on V ⁇ circumflex over ( ) ⁇ typ
  • ⁇ 6 describes the changes in V ⁇ circumflex over ( ) ⁇ typ that was not accounted for by changes in BSA.
  • Body weight, BSA, and BSA 2 were tested for inclusion into the Full Model for V ⁇ circumflex over ( ) ⁇ typ . BSA 2 was chosen because it produced the lowest objective function values.
  • V ⁇ circumflex over ( ) ⁇ typ ⁇ 5 *BSA 2 Eq. 10 TABLE 5 Estimates for Population Model Parameters Parameters Estimate CV, % 95% Confidence interval ⁇ 1 26.2 (mL/h*m 2 ) 2.70% 24.6-27.4 (ml/h*m 2 ) ⁇ 4 0.31 7.90% 0.26-0.36 ⁇ 5 5.13 (L/m 4 ) 4.40% 4.49-5.57 (l/m 4 ) k ⁇ circumflex over ( ) ⁇ typ, (Male) 0.0026 (hr ⁇ 1 ) 7.3% 0.0023-0.0030 (hour ⁇ 1 ) k ⁇ circumflex over ( ) ⁇ typ, 0.0022 (hr ⁇ 1 ) 4.7% 0.0020-0.0024 (hour ⁇ 1 ) (Female)
  • Equation 11 The following discussion is offered as an example to use Equation 11 to calculate the suramin dose that would yield the target concentration of 15 ⁇ M or 21.4 ⁇ g/ml at 48 hours. Substituting 21.4 ⁇ g/ml for Cp and 48 hours for t, the Population Model values for V and the numerical values of k ⁇ circumflex over ( ) ⁇ typ into Equation 11 yielded Equation 15.
  • FACTOR The numerical values of FACTOR were calculated to be 125 mg/m 4 for males and 123 mg/m 4 for females. Because of the relatively small difference (i.e., ⁇ 2%) in the FACTOR values for the two genders, and for the ease of dose calculation, the value of FACTOR was set at 125 mg/m 4 for both genders. A larger gender-related difference (e.g., >10%) would require different FACTOR values for the two genders.
  • Chemotherapy is usually given in multiple cycles, e.g., weekly or every three weeks. Suramin is eliminated from the body very slowly. The data in non-small lung cancer patients show a long plasma half-life for suramin (about 11 days). Hence, a considerable fraction of the previous dose remains in the body at the time of the second and subsequent treatments (i.e., day 8 in weekly treatment regime or day 22 on every 3 week treatment regime). As a result, the suramin dose for second and subsequent treatment cycles has to be adjusted for the residual suramin.
  • Cp 48 hr target plasma concentration at 48 hours and equaled to 15 ⁇ M or 21.4 ⁇ g/ml.
  • Cp 48 hr, observed is the concentration observed at 48 hours.
  • Dose accuracy between the PBPK method-predicted dose and Ideal Dose was calculated using Equation 18.
  • Dose accuracy, % Predicted dose Ideal Dose * 100 ⁇ ⁇ % Eq . ⁇ 18
  • the dose calculated by the PBPK method was 106 ⁇ 15% of the Ideal Dose.
  • the dose calculated by the BSA method was 103 ⁇ 7% of the Ideal Dose. The good agreement between the model-predicted dose and the Ideal Dose indicates a good predictive power of the PBPK method.
  • Additional pharmacokinetic analysis e.g., by simulation, indicated two approaches to obtain the desired maximum concentration of about or below 50 ⁇ M while maintaining the 48-hour concentration at about 10 ⁇ M.
  • One approach is to divide the total calculated suramin dose into two portions, the first portion equaling two-thirds (2 ⁇ 3) of the total dose given prior to chemotherapy, followed by the remaining one-third (1 ⁇ 3) of the dose given 24 hours later.
  • the second approach is to give the total suramin dose all at once, wait for about 2 to about 4 hours, when the suramin concentration declines to about or below 50 ⁇ M, and then administer a chemotherapeutic agent.
  • Concentration accuracy, % ( Cp 48 ⁇ ⁇ hr , observed - Cp 48 ⁇ ⁇ hr , target ) Cp 48 ⁇ ⁇ hr , target * 100 ⁇ % Eq . ⁇ 19
  • Table 6 shows the results.
  • the 48-hour plasma concentrations in all treatments were above 10 ⁇ M.
  • the maximum concentrations after administration of another chemotherapeutic agent, i.e., paclitaxel, in all treatments were below 50 ⁇ M.
  • the difference between the target and observed plasma concentrations of 15 ⁇ M at 48 hours were ⁇ 17%.
  • both the first and subsequent cycle doses can be calculated based on the target concentrations at target time points, and the squared value of body surface area and gender of the patient.
  • a nomogram can be developed to calculate the target suramin dose.
  • a nomogram facilitates the dose determination in a clinical setting, e.g., community medical offices.
  • the target suramin concentrations were 50 ⁇ M immediately after administration of another chemotherapeutic agent and 15 ⁇ M at 48 hours, and the k values were 0.0026 hour ⁇ 1 for males and 0.0022 hour ⁇ 1 for females.
  • the numerical values of FACTOR were calculated to be 125 mg/m 4 for males and 123 mg/m 4 for females. Because of the relatively small difference (i.e., ⁇ 2%) in the FACTOR values for the two genders, and for the ease of dose calculation, the value of FACTOR was set at 125 mg/m 4 for both genders. A larger gender-related difference (e.g., >10%) would require different FACTOR values for the two genders.
  • FACTOR is a function of the target concentration Cp, k value and t, which is the time when the target concentration is attained.
  • FACTOR can be calculated based on the desired target concentration attained at the desired time t.
  • FACTOR can be calculated based on the desired Cp at time t and the k values.
  • FACTOR for a weekly treatment schedule can be calculated using a t value of 168 hours, and a t value of 504 hours for an every-3-week treatment schedule.
  • the FACTOR can be calculated for different target concentrations, e.g., 10 or 20 ⁇ M.
  • the FACTOR can also be used to adjust for the variation in treatment time, e.g., delay in treatment due to the travel schedule of patients. For example, if the second cycle is initiated 25 days after the administration of the first dose during the previous first cycle, the value of the FACTOR is 87 for a man and 79 for a woman, whereas the values of FACTOR are 80 for a man and 72 for a woman who receive treatments every three weeks (i.e., 21 days after the administration of the first dose during the previous cycle). Likewise, for a weekly schedule, the amount of residual suramin is greater than that after an every-3-week schedule. Accordingly, the FACTOR values are smaller, at 39 for males and 33 for females.
  • the methods described above use a target suramin concentration range of between 10 to 50 ⁇ M over 48 hours. This is specific for situations where the other chemotherapeutic agents to be used in combination with suramin have half-lives of less than 12 hours and, therefore, would be more than 90% eliminated in 48 hours.
  • This same method for calculating the chemosensitization dose of suramin can be extended to other situations where the chemotherapeutic agents have longer half-lives. In this case, the target suramin concentrations will need to be maintained for at least four half-lives of the other chemotherapeutics.
  • the suramin dose can be calculated from Equations 15 and 16, by substituting the time parameter, e.g., from 48 hours to the new target time (e.g. three to four times the terminal half-lives of the co-administered chemotherapeutic agent). The modified equations can then be used to calculate appropriate nomograms.
  • this example together with the results of Examples I through III, have demonstrated an approach to use PBPK analysis and a method to determine or calculate the suramin dose that produces chemosensitization in animals and in humans.
  • the suramin dose calculated using this method would yield the desired target plasma concentrations over the duration when other chemotherapeutic agents are present in the plasma at therapeutically significant levels.
  • the suramin dose calculated using this method would not yield plasma concentrations that do not produce chemosensitization.
  • the use of PBPK analysis to determine the suramin dose that produces chemosensitization can be expanded to evaluate other patient characteristics, including, but not limited to, race, pre-adulthood vs. adulthood. The same method can also be applied to nonhuman patients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US10/807,620 2001-09-24 2004-03-24 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy Abandoned US20040180955A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/807,620 US20040180955A1 (en) 2001-09-24 2004-03-24 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy
US13/031,306 US8580857B2 (en) 2001-09-24 2011-02-21 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US32470401P 2001-09-24 2001-09-24
PCT/US2002/030210 WO2003026574A2 (en) 2001-09-24 2002-09-24 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy
US10/807,620 US20040180955A1 (en) 2001-09-24 2004-03-24 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/030210 Continuation-In-Part WO2003026574A2 (en) 2001-09-24 2002-09-24 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/031,306 Division US8580857B2 (en) 2001-09-24 2011-02-21 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy

Publications (1)

Publication Number Publication Date
US20040180955A1 true US20040180955A1 (en) 2004-09-16

Family

ID=23264730

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/807,620 Abandoned US20040180955A1 (en) 2001-09-24 2004-03-24 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy
US13/031,306 Expired - Fee Related US8580857B2 (en) 2001-09-24 2011-02-21 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/031,306 Expired - Fee Related US8580857B2 (en) 2001-09-24 2011-02-21 Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy

Country Status (9)

Country Link
US (2) US20040180955A1 (OSRAM)
EP (1) EP1429713A4 (OSRAM)
JP (1) JP2005508322A (OSRAM)
KR (1) KR20040062546A (OSRAM)
CN (1) CN100441176C (OSRAM)
AU (1) AU2002330088B2 (OSRAM)
CA (1) CA2461227C (OSRAM)
IL (1) IL161036A0 (OSRAM)
WO (1) WO2003026574A2 (OSRAM)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6905669B2 (en) 2001-04-24 2005-06-14 Supergen, Inc. Compositions and methods for reestablishing gene transcription through inhibition of DNA methylation and histone deacetylase
US6982253B2 (en) 2002-06-05 2006-01-03 Supergen, Inc. Liquid formulation of decitabine and use of the same
US20050043233A1 (en) 2003-04-29 2005-02-24 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US7250416B2 (en) 2005-03-11 2007-07-31 Supergen, Inc. Azacytosine analogs and derivatives
US7700567B2 (en) 2005-09-29 2010-04-20 Supergen, Inc. Oligonucleotide analogues incorporating 5-aza-cytosine therein
WO2007065016A2 (en) * 2005-12-02 2007-06-07 Au Jessie L S Methods and compositions to improve activity and reduce toxicity of stents
KR20150091434A (ko) * 2007-07-30 2015-08-10 아디아 바이오사이언스즈 인크. 다형체를 포함하는, ｍｅｋ의 억제제로서의 ｎ-(아릴아미노) 술폰아미드의 유도체 및 조성물, 사용 방법 및 이의 제조 방법
US9381207B2 (en) 2011-08-30 2016-07-05 Astex Pharmaceuticals, Inc. Drug formulations
CN104398517A (zh) * 2014-11-28 2015-03-11 四川大学 乙胺嘧啶的新用途及治疗肿瘤的药物组合物
CA2991167A1 (en) 2015-07-02 2017-01-05 Otsuka Pharmaceutical Co., Ltd. Lyophilized pharmaceutical compositions
TW201718598A (zh) * 2015-08-27 2017-06-01 美國禮來大藥廠 Ｅｚｈ２抑制劑
CA3071755A1 (en) 2017-08-03 2019-02-07 Otsuka Pharmaceutical Co., Ltd. Drug compound and purification methods thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5597830A (en) * 1994-12-20 1997-01-28 Warner-Lambert Company Combination chemotherapy
US20020111362A1 (en) * 1999-10-15 2002-08-15 Joseph Rubinfeld Inhibition of abnormal cell proliferation with camptothecin and combinations including the same
US6599912B1 (en) * 1999-06-03 2003-07-29 Jessie L. -S. Au Methods and compositions for modulating cell proliferation and cell death
US6855338B2 (en) * 1997-03-11 2005-02-15 Les Laboratoires Aeterna, Inc. Anti-tumor therapies comprising a combination of a cartilage extract and an anti-neoplastic agent providing high efficacy and low toxic side effects
US6900235B1 (en) * 1997-05-16 2005-05-31 Uaf Technologies And Research, Llc Benzimidazole compounds, and pharmaceutical compositions and unit dosages thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040097250A (ko) * 1996-05-24 2004-11-17 유니버시티 오브 브리티시 콜롬비아 신체 통로의 질병을 치료 또는 예방하기 위한 조성물 및방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5597830A (en) * 1994-12-20 1997-01-28 Warner-Lambert Company Combination chemotherapy
US6855338B2 (en) * 1997-03-11 2005-02-15 Les Laboratoires Aeterna, Inc. Anti-tumor therapies comprising a combination of a cartilage extract and an anti-neoplastic agent providing high efficacy and low toxic side effects
US6900235B1 (en) * 1997-05-16 2005-05-31 Uaf Technologies And Research, Llc Benzimidazole compounds, and pharmaceutical compositions and unit dosages thereof
US6599912B1 (en) * 1999-06-03 2003-07-29 Jessie L. -S. Au Methods and compositions for modulating cell proliferation and cell death
US20020111362A1 (en) * 1999-10-15 2002-08-15 Joseph Rubinfeld Inhibition of abnormal cell proliferation with camptothecin and combinations including the same

Also Published As

Publication number Publication date
WO2003026574A3 (en) 2004-04-15
WO2003026574A2 (en) 2003-04-03
CA2461227C (en) 2012-05-15
CN100441176C (zh) 2008-12-10
IL161036A0 (en) 2004-08-31
EP1429713A4 (en) 2007-08-08
JP2005508322A (ja) 2005-03-31
KR20040062546A (ko) 2004-07-07
CA2461227A1 (en) 2003-04-03
EP1429713A2 (en) 2004-06-23
US8580857B2 (en) 2013-11-12
AU2002330088B2 (en) 2009-09-03
CN1589138A (zh) 2005-03-02
HK1074167A1 (zh) 2005-11-04
US20110142794A1 (en) 2011-06-16

Similar Documents

Publication Publication Date Title
US8580857B2 (en) Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy
US20250228861A1 (en) Cancer Treatments Using MTA-Cooperative PRMT5 Inhibitors
Nichols et al. Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol.
Infante et al. A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours
Venook et al. Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264.
EP3038647B1 (en) Combination therapy for the treatment of glioblastoma
US8178564B2 (en) Use of picoplatin to treat colorectal cancer
US20190233523A1 (en) Combination therapy for cancer
AU2002330088A1 (en) Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy
JP2008501654A (ja) シスプラチンとｅｇｆｒ阻害剤を用いた治療
US20120196828A1 (en) Sensitization of cancer cells to treatment
US8173686B2 (en) Use of picoplatin to treat colorectal cancer
Kelsen et al. A phase I trial of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic 5‐fluorouracil and levamisole after resection of high risk colon cancer
TWI451875B (zh) 用於治療先前治療過之乳癌之抗－血管新生療法
US8168661B2 (en) Use of picoplatin to treat colorectal cancer
CA3213804A1 (en) Wee1 compound for treating uterine serous carcinoma
US20210379095A1 (en) Methods and Combination Therapy to Treat Biliary Tract Cancer
TW201717926A (zh) 用於治療尤文氏家族腫瘤(ewing family tumors)的組成物及方法
KR20220101120A (ko) 화학요법 연관 악액질 및 심장독성의 치료 및 예방을 위한 요오드 화합물의 용도
US20190117655A1 (en) Treatment of Biliary Duct Cancer
HK1074167B (en) Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy
US20080064665A1 (en) Combination approaches to cancer treatment
RU2793543C2 (ru) Способы и комбинированное терапевтическое средство для лечения рака желчных протоков
Bayoglu et al. Uracil/tegafur as a possible salvage therapy in chemo-refractory colorectal cancer patients: A single institutional retrospective study
HK40121791A (zh) 利用mta协作的prmt5抑制剂的癌症治疗

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- AFTER EXAMINER'S ANSWER OR BOARD OF APPEALS DECISION