US20030050297A1 - Cancer therapy - Google Patents

Cancer therapy Download PDF

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US20030050297A1
US20030050297A1 US10/051,367 US5136702A US2003050297A1 US 20030050297 A1 US20030050297 A1 US 20030050297A1 US 5136702 A US5136702 A US 5136702A US 2003050297 A1 US2003050297 A1 US 2003050297A1
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mimetic
manganese
mntbap
sod
lung
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James Crapo
Brian Day
Ines Batinic-Haberle
Richard Gammans
Zeljko Vujaskovic
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GOODNOW CAPITAL LLC
National Jewish Health
Aeolus Sciences Inc
Duke University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • 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
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates, in general, to cancer therapy, and, in particular, to a method of preventing or treating cancer using low molecular weight antioxidants (e.g., mimetics of superoxide dismutase (SOD)) as the active agent or as a chemo- and/or radio-protectant.
  • low molecular weight antioxidants e.g., mimetics of superoxide dismutase (SOD)
  • SOD superoxide dismutase
  • the invention also relates to compounds and compositions suitable for use in such a method.
  • Oxidants are produced as part of the normal metabolism of all cells but also are an important component of the pathogenesis of many disease processes.
  • Reactive oxygen species for example, are critical elements of the pathogenesis of diseases of the lung, the cardiovascular system, the gastrointestinal system, the central nervous system and skeletal muscle.
  • Oxygen free radicals also play a role in modulating the effects of nitric oxide (NO.). In this context, they contribute to the pathogenesis of vascular disorders, inflammatory diseases and the aging process.
  • SODs superoxide dismutases
  • CuZn SOD dimeric copper- and zinc-containing enzyme
  • a second is a tetrameric manganese-containing SOD (Mn SOD) found within mitochondria
  • the third is a tetrameric, glycosylated, copper- and zinc-containing enzyme (EC-SOD) found in the extracellular fluids and bound to the extracellular matrix.
  • Mn SOD manganese-containing SOD
  • EC-SOD tetrameric, glycosylated, copper- and zinc-containing enzyme
  • the present invention provides methods of cancer prevention and therapy that involve the use of low molecular weight mimetics of SOD.
  • the present invention relates to a method of modulating intra- or extracellular levels of oxidants.
  • the invention relates to a method of protecting normal tissue of a cancer patient from the toxic effects associated with gene therapy, immunotherapy, chemotherapy and/or radiation therapy using mimetics of SOD.
  • the invention relates to a method of preventing or treating cancer in a patient in need of such treatment using low molecular weight antioxidants.
  • the invention additionally relates to agents suitable for use in such methods, including methine (ie, meso) substituted porphyrins and tetrapyrroles.
  • FIGS. 1 A- 1 H show the structures of certain generic and specific definitions of compounds suitable for use in the present invention.
  • mimetics of the invention can be of Formula I or Formula II, or dimeric forms thereof, an example of a dimeric form being shown in FIG. 1D.
  • SOD activities of certain of the depicted compounds are shown in Table 1 (as measured by the cytochrome C method): TABLE 1 Compound SOD activity (U/mg) 10110 225 10113 10,648 10123 17,061 10143 14,038 10150 14,789 10153 23,467 10158 14,342 CuZn-SOD 2,200
  • FIGS. 2 A- 2 C B16 melanoma tumor treated with SOD mimetic.
  • the mimetic was 10113 at a dose of 6 mg/kg given intraperitoneally qd for 5 days.
  • FIG. 2B Mammary adenocarcinoma treated with SOD mimetic. 10113 was given intraperitoneally at a dose of 6 mg/kg/day for 16 days. Radiation therapy (RT), 21 Gy, was given on day 8 or 9.
  • RT Radiation therapy
  • FIG. 3 Tumor growth inhibition using tumor growth delay assay in Fisher 344 rats after intraperitoneal administration of 6 mg/kg of three different compounds.
  • FIG. 4 Animals were pretreated with different SOD mimetics (6 mg/kg i.p.) 24 hours before implantation of 2.5 mil./ml R3230 mammary adenocarcinoma cells in Z-chambers. Significant (p ⁇ 0.01) inhibition of tumor development was observed in animals treated with 10113 (manganese(III)tetrakis(N-ethylpyridinium-2-yl)porphyrin) and 10150 (manganese(III)tetrakis(N-diethylimidazolium-2,5-yl)porphyrin) compounds.
  • FIG. 5 Antiangiogenesis: Animals were pretreated with different SOD mimetics (6 mg/kg i.p.) 24 hours before implantation of 2.5 mil./ml R3230 mammary adenocarcinoma cells in Z-chambers. Significant inhibition of tumor angiogenesis was observed in animals treated with 10113 compound.
  • FIG. 6 shows the chemical structure of a catalytic antioxidant, manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP).
  • FIG. 7 shows the pharmacokinetic profile of MnTBAP in mice given a single 10 mg/kg, ip dose.
  • MnTBAP levels in serum (closed squares) and lung tissue (open squares) were measured at 0.3, 0.5, 1, 2, 4, 6 and 24 hours after drug treatment. Results are the means of 3 mice ⁇ SEM. Data were calculated from curve-fitted data assuming a two-compartment pharmacokinetic model. MnTBAP rapidly equilibrated into the blood stream and the lungs of mice.
  • FIG. 8 shows that MnTBAP attenuates bleomycin-induced weight loss in mice.
  • Control phosphate buffered saline 1 ml/kg, ip, twice daily; open square
  • MnTBAP 5 mg/kg, ip, twice daily; open triangle
  • Bleomycin (closed triangle) treated mice had significantly more weight loss than control mice and this was attenuated in the bleomycin plus MnTBAP (closed diamond) treated mice after 5 days of treatment and continued to the end of the study. Results are the means of 5 mice ⁇ SEM.
  • FIGS. 9A and 9B show that MnTBAP attenuates bleomycin-induced airway constriction and collagen accumulation.
  • FIG. 9A Whole body barometric plethysmography was employed and enhanced pause (P ENH ) was used as a non-invasive index of airway dysfunction. Control (phosphate buffered saline, 1 ml/kg, ip, twice daily; open bar) and MnTBAP (5 mg/kg, ip, twice daily; hatched bar) treated mice had similar P ENH values after 14 days of treatment.
  • P ENH enhanced pause
  • FIG. 9B Lung fibrosis was biochemically assessed using hydroxyproline as an index of collagen accumulation. Control and MnTBAP treated mice had similar hydroxyproline values after 14 days of treatment. Bleomycin treated mice had significantly elevated hydroxyproline values compared to control mice and this was attenuated in the bleomycin plus MnTBAP treated mice. Results are the means of 5 mice ⁇ SEM. Bars with different letters are significantly different from one another, p ⁇ 0.05.
  • FIGS. 10 A- 10 H show that MnTBAP attenuates bleomycin-induced pulmonary injury.
  • Mice were treated with phosphate buffered saline (PBS, 1 ml/kg, ip, twice daily for 14 days), MnTBAP (5 mg/kg, ip, twice daily for 14 days, bleomycin (3.5 U/kg, it, once) or bleomycin plus MnTBAP and killed after 14 days.
  • Lungs were inflation fixed in 10% neutral buffered formalin. Five-micron thick sections were stained with hematoxylin and eosin and examined microscopically.
  • FIG. 10A Representative lung section from a PBS/PBS treated mouse.
  • FIG. 10B Representative lung section from a PBS/PBS treated mouse.
  • FIG. 10C Representative lung, section from a bleomycin/PBS treated mouse.
  • FIG. 10D Representative lung section from a bleomycin/MnTBAP treated mouse. Bar represents 100 microns. Five-micron thick sections were stained with Masson trichrome and examined microscopically.
  • FIG. 10E Representative lung section from a bleomycin/PBS treated mouse.
  • FIG. 10F Representative lung section from a bleomycin/MnTBAP treated mouse.
  • FIG. 10G Representative lung section from a PBS/PBS treated mouse.
  • FIG. 10H Representative lung section from a PBS/MnTBAP treated mouse. Bar represents 20 microns.
  • FIG. 11 MnTBAP attenuates bleomycin-induced lung injury as determined by histopathologic analysis. Mice were treated with either bleomycin (3.5 U/kg, it) or phosphate buffered saline (PBS, 50 ⁇ l) and then given MnTBAP (5 mg/kg, ip, twice daily) or PBS (1 ml/kg, ip, twice daily) for 14 days. Lungs were inflation fixed in 10% neutral buffered formalin. Five-micron thick sections were stained with hematoxylin and eosin or Masson Trichrome and examined microscopically. Slides were systematically scanned in a microscope using a ⁇ 10 objective.
  • PBS phosphate buffered saline
  • Each successive field was individually assessed for severity of interstitial fibrosis and allotted a score between 0 and 8 using a predetermined scale of severity. Scores from the fields were averaged to obtain a pathologic score for each animal. Bars with asterisks are statistically different from the PBS/PBS group (p ⁇ 0.05). A dagger indicates a significant interaction between MnTBAP and bleomycin (p ⁇ 0.05).
  • FIG. 12 Changes in breathing rates over 6 months after 28 Gy of right hemithoracic irradiation with and without MnTE-2-PyP (AEOL 10113) (LOCF data set) vs. Control (no radiation).
  • FIGS. 13A and 13B Assessment of post radiation lung fibrosis. Hydroxy-proline content of upper right lung lobe per gram of wet lung 6 months after 28 Gy of right hemithoracic irradiation.
  • FIG. 13B Fibrosis score from histopathology. Results are means of 5 rats ⁇ SEM.
  • FIG. 14 Relative changes in plasma levels of TGF- ⁇ after 28 Gy of right hemothoracic irradiation.
  • FIG. 16 A549 cells were grown 50% confluence in 24 well plates in complete media. Cells were then incubated for 24 hours with the above concentrations of drug and 3 H-thymidine (to assess DNA synthesis). After three washes in PBS, the cells were homogenized and the radioactivity counted. At 4 ⁇ M MnTE-2-PyP, there was a 50% inhibition of incorporation of 3 H-thymidine.
  • FIGS. 17 A- 17 E Effect of metalloporphyrins on human tumor cell (A549).
  • FIG. 18 Distribution of mucositis scores over time.
  • FIG. 19 Effect of SOD mimetic on the percent of days with mucositis scores ⁇ 3.
  • the present invention relates to methods of preventing or treating cancer using low molecular weight antioxidants (eg mimetics of scavengers of reactive oxygen species, including mimetics of SODs, catalases and peroxidases) as the active agent or as a chemo- and/or radio-protectant.
  • low molecular weight antioxidants eg mimetics of scavengers of reactive oxygen species, including mimetics of SODs, catalases and peroxidases
  • the invention further relates to formulations suitable for use in such methods.
  • Mimetics of scavengers of reactive oxygen species appropriate for use in the present methods include methine (ie meso) substituted porphines and substituted tetrapyrroles, or pharmaceutically acceptable salts thereof (eg chloride or bromide salts).
  • the invention includes both metal-free and metal-bound porphines and tetrapyrroles.
  • metal-bound porphines and tetrapyrroles manganic derivatives are preferred, however, metals other than manganese such as iron (II or III), copper (I or II), cobalt (II or III), or nickel (I or II), can also be used.
  • the metal selected can have various valence states, for example, manganese II, III, IV or V can be used.
  • Zinc (II) can also be used even though it does not undergo a valence change and therefore will not directly scavenge superoxide.
  • the choice of the metal can affect selectivity of the oxygen species that is scavenged. Examples of such mimetics are shown in FIG. 1 and are described in U.S. Pat. Nos. 5,994,339, 6,127,356 and 6,103,714 and in U.S. application Ser. Nos. 09/184,982 and 09/880,124, 09/296,615, 09/490,537 and 09/880,075 (No. 60/211,857) (these patents and applications are incorporated in their entirety by reference). Appropriate methods of synthesis are described in these patents and applications.
  • manganese salen compounds can also be used (Baudry et al, Biochem. Biophys. Res. Commun. 192:964 (1993)).
  • Manganese macrocyclic complexes such as those described by Riley et al (Inorg. Chem. 35:5213 (1996)), Deune et al (Plastic Reconstr. Surg. 98:712 (1996)), Lowe et al (Eur. J. Pharmacol. 304:81 (1996)) and Weiss et al (J. Biol. Chem. 271:26149 (1996)) can also be used.
  • Cancer types amenable to treatment in accordance with the invention include leukemias, myelomas, and solid tumors such as melanomas, lymphomas, sarcomas, and tumors of the lung, breast, prostate and colon.
  • the compounds described herein can also be used as chemopreventatives, for example, in individuals diagnosed with preneoplastic conditions such as squamous metaplasia cervical displasia, and polyposis of the colon.
  • the present compounds can be administered to individuals predisposed to cancer or in remission in order to reduce the likelihood of tumor development.
  • the compounds of the invention can be used alone or in combination with other chemotherapeutic agents, such as bleomycin, cisplatin, adriamycin, and camptothicen.
  • chemotherapeutic agents such as bleomycin, cisplatin, adriamycin, and camptothicen.
  • the present compounds can increase the anti-tumor effect of chemotherapy as well as prevent toxicity, in whole or in part, resulting from free radicals produced by agents such as bleomycin, cisplatin and adriamycin.
  • the present compounds can also be used in combination with radiation therapy and can both increase the efficacy of radiation therapy and serve to protect normal tissue from the effects of radiation treatment.
  • the mimetics can further be used together with heat therapy, gene therapy, immunotherapy, or any combination of the above anti-tumor therapies, and improve the toxic/therapeutic ratio through increasing the anti-tumor effect and reducing toxicity to normal tissue by preventing damage (e.g., inflammation) resulting from free radical generation.
  • damage e.g., inflammation
  • a wide variety of normal tissues can be protected through the use of the present mimetics, including lung tissue, mucosa, gastrointestinal tract tissue, leucocytes, hair follicles, skin and bone marrow.
  • compositions suitable for use in the present methods can be formulated into pharmaceutical compositions suitable for use in the present methods.
  • Such compositions include the active agent (mimetic) together with a pharmaceutically acceptable carrier, excipient or diluent.
  • the composition can be present in dosage unit form for example, tablets, capsules or suppositories.
  • the composition can also be in the form of a sterile solution suitable for injection (e.g., subcutaneous, i.p. or i.v.) or nebulization.
  • Compositions can also be in a form suitable for opthalmic use.
  • the invention also includes compositions formulated for topical administration, such compositions taking the form, for example, of a lotion, cream, gel or ointment.
  • the concentration of active agent to be included in the composition can be selected based on the nature of the agent, the dosage regimen and the result sought.
  • the compounds can also be encapsulated in lysosomes and thereby targeted to enhance delivery to tumors.
  • the dosage of the composition of the invention to be administered can be determined without undue experimentation and will be dependent upon various factors including the nature of the active agent (including whether metal bound or metal free), the route of administration, the patient, and the result sought to be achieved.
  • a suitable dosage of mimetic to be administered IV or topically can be expected to be in the range of about 0.01 to 50 mg/kg/day, preferably, 0.1 to 10 mg/kg/day, more preferably 0.1 to 6 mg/kg/day.
  • For aerosol administration it is expected that doses will be in the range of 0.001 to 5.0 mg/kg/day, preferably, 0.01 to 1 mg/kg/day. Suitable doses will vary, for example, with the compound and with the result sought.
  • TRT thoracic irradiation
  • NSCLC non-small cell lung cancer
  • Tumor control rates are very low with this dosage, however.
  • the clinical problem is that local control is a sine qua non for disease cure. Higher doses have resulted in better local control rates, often with increased complications.
  • Pulmonary toxicity from thoracic irradiation is also a significant problem in other settings including: combined modality treatment of Hodgkin's disease and esophageal cancer, chest wall irradiation after high dose chemo/ABMT (autologous bone marrow transplantation) in breast cancer, and bone marrow transplantation with total body irradiation.
  • chemo/ABMT autologous bone marrow transplantation
  • SOD superoxide dismutase
  • MnTE-2-PyP manganese(III) tetrakis(N-ethylpyridinium-2-yl)porphyrin
  • mice with human melanoma tumors B 16
  • Tumor doubling time in the control group of animals was 2 days whereas in animals receiving treatment, tumor-doubling time increased to 4 days.
  • Therapeutic advantage from the modifier of radiation-induced normal tissue injury can only be achieved if the radioprotective agent does not also protect the tumor.
  • FIG. 2C A similar experiment (FIG. 2C) demonstrated that AEL 10113 treatment limited tumor growth and did not diminish the effect of radiation on tumor growth.
  • R3230 AC mammary adenocarcinoma was transplanted on the right hind leg.
  • the rats were randomized into 4 groups to receive 1) Saline (control); 2) Drug 10150; 3) Drug 10113; 4) Drug 10201.
  • Drugs were given daily in dose of 6 mg/g i.p.
  • the tumor size was measured twice a week. (FIG. 3).
  • the Fibrin Z-Chambers have fibrinogen solution poured inside the chamber through the pore and followed by 2 units of thrombin.
  • first R3230 Ac rat mammary carcinoma cells grown in tissue culture were harvested by standard procedures and the resultant pellet was washed three times with DMEM.
  • Fibrinogen solution was added to the pellet to make the final concentration of cells approximately 2.5 million cells/ml.
  • This tumor cell/fibrinogen solution was added to the chambers through the pore and again followed by 2 units of thrombin. After addition of thromin, fibrin was allowed to gel inside the chambers for 15 minutes before implantation in animals.
  • Fischer 344 rats were anesthetized, hair was removed using clippers and the surface was surgically prepared. Two small incisions were made in the dorsum along the midline about 4 cm apart. Fascia was blunt dissected and small pockets were created on both sides along the midline incisions. Four Z-chambers were successfully implanted in those pockets per animal. There is little difference in response (amount of granulation or tumor tissue generated) between the 4 chambers/animal and among the chambers/animals in one group. Also, no difference in response has been observed whether 1 or 4 chambers (Fibrin or Tumor Z-chambers) are implanted per animal in initial studies with this model system.
  • the Z-Chambers were harvested on day 1 or 12 post surgery. The tissues were cut out from the chamber and were preserved in 10% formalin for paraffin embedding. For evaluation of the Z-Chambers, pictures of the sections of each sample stained with hematoxylin and eosin were taken at 10 ⁇ . Pictures were taken at the maximum depth of tissue observed in the section. The depth of either the tumor tissue (tumor growth) or granulation tissue (wound healing) was measured with calipers on the 4 ⁇ 6 inch print. In this way of measurement, bias has purposefully been given to the treated tissue since in many treated samples the tissue never homogenously filled the chamber at that depth. All measurements were done in a blinded fashion. (FIG. 4)
  • Immunohistochemistry was carried out using procedures described by Hsu et al (Hsu et al., j. Histochem. Cytochem. 29:577-580 (1981)). Briefly, paraffin embedded tissues were sectioned (5 microns) and antigen retrieval was performed using citrate buffer from Biogenex (San Ramon, Calif.). Tissues were treated with primary antibody against tissue transglutaminase (TG100, 1:10, endothelial cell marker, non-reactive to Factor XIIIa) (Neomarkers, CA) for 1 hour at 37° C.
  • tissue transglutaminase TG100, 1:10, endothelial cell marker, non-reactive to Factor XIIIa
  • Hematoxylin & Eosin and Masson's trichrome was carried out as described by Sheehan (Sheehan et al, In: Theory and Practice of Histotechnology, Battelle Press, Columbus, Ohio (1980)) to evaluate collagen (green color) on the fibrin Z-chamber sections.
  • Microvessel density was calculated as described by Weidner et al (Weidner et al, J. New Engl. J. Med. 324:1-8 (1991)). Briefly, six hot spots or areas with highest vessels marked by the vessel marker at a high power field (400 ⁇ ) per sample section were selected and number of blood vessel counted. The data was then pooled for the control and treated tissues to arrive at the mean values for each group. All measurements were done by two independent pathologists in a blinded fashion. (FIG. 5)
  • mice that were 6-8 weeks of age were utilized in these studies (Taconic, Germantown, N.Y.). Mice were acclimated to 22° C. in an environmentally controlled room (12-hr light cycles) at least 6 days prior to treatment. Toxicity studies were employed using a moving average method previously described by Weil (Weil, Biometrics 8:249-263 (1952)). Groups of 4 mice were given MnTBAP (50, 88, 153 and 268 mg/kg, ip) and observed over a 48 hour time period.
  • MnTBAP 50, 88, 153 and 268 mg/kg, ip
  • mice were given one bolus dose of MnTBAP (10 mg/kg, ip) dissolved in phosphate buffered saline (PBS) and blood and lung tissue levels of MnTBAP were determined at several different time points for pharmacokinetic analysis. Separate sets of mice were used for the lung fibrosis study. Mice were randomized into two groups of 10 mice that received intratracheal bleomycin (3.5 U/kg, ICN, Aurora, Ohio) or an equivalent volume of saline (50 ⁇ l). Half the animals in these groups also received MnTBAP (5 mg/kg, ip) or an equivalent volume of PBS (1 ml/kg, ip) twice daily for 14 days.
  • PBS phosphate buffered saline
  • mice were anesthetized with pentobarbital (60 mg/kg, ip) and blood was obtained by a cardiac puncture. Blood samples were placed in 1.5 ml tubes and left at room temperature to clot for 30 minutes. Serum was removed after spinning the blood samples at 1000 ⁇ g for 10 minutes. Serum samples were stored at ⁇ 20° C. until used. Lungs were perfused with phosphate buffered saline through the pulmonary artery to clear blood from the vasculature. The lungs were removed and homogenized in 10 mM tris-HCl buffer containing 1.15% potassium chloride at pH 7.5 with a polytron (Turrax-25, Janke & Kunkel, Germany).
  • the stationary phase consisted of a YMC ODS C-18 column (1.4 ⁇ 100 mm) and a mobile phase consisting of 60% solution A and 40% solution B (solution A: water +0.1% trifluoroacetate, solution B: acetonitrile/water (90:10)+0.1% trifluoroacetate).
  • MnTBAP extracted from lung homogenates and serum eluted at 5.9 minutes. Recovery of MnTBAP from samples using the extraction method described above ranged from 85-91%. The linear regression analysis of the standard curves were r 2 >0.99.
  • the lungs were dried at 80° C. until a constant weight is obtained.
  • the dried lungs were hydrolyzed under vacuum in a glass vial in 1 ml of 12 N HCl at 120° C. overnight.
  • the samples were lyophilized and assayed for hydroxyproline content using chloramine-T as previously described (Woessner, Arch. Biochem. Biophys. 93:440-447 (1961)).
  • the lungs were fixed in 4% paraformaldehyde for 24 hours and then processed for paraffin embedding. Sections of lung were stained with routine hematoxylin and eosin or with a Masson trichrome stain to assess the degree of fibrosis. The extent of lung injury and fibrosis was graded by four pathologists, blinded as to the treatment group, on a scale of one (no injury) to ten (severe injury/fibrosis). The major criteria examined included interstitial thickening, collagen deposition, type 2 cell hyperplasia, and inflammatory cell infiltration.
  • MnTBAP catalytic antioxidant
  • FIG. 6 To test the efficacy of the catalytic antioxidant MnTBAP (FIG. 6) in a model of pulmonary fibrosis, it was necessary to establish a rationale dosing regiment that would result in MnTBAP lung levels without drug toxicity. MnTBAP toxicity was assessed using a moving average method that consisted of four geometric dose groups (50, 88, 153 and 268 mg/kg, ip) of 4 mice each over 48 hours. There were no deaths associated with the 50 mg/kg group and 1 death in the 88 mg/kg group. The two highest doses were lethal to the mice. MnTBAP had a calculated LD 50 of 100 mg/kg with a 95% confidence interval of 98-104 mg/kg.
  • MnTBAP 10 mg/kg ip dose of MnTBAP was then chosen to conduct pharmacokinetic studies based on the toxicity data. Serum and lung tissue levels of MnTBAP were determined at 0.3, 0.5, 1, 2, 4, 6 and 24 hours after drug treatment. The data was fitted to a two compartment pharmacokinetic model and the distribution and elimination half-lives were calculated from the data fitted curves (FIG. 7). MnTBAP rapidly equilibrated into the lung from the bolus ip injection with a distribution half-life of 14 minutes (Table 2). The estimated peak serum and lung tissue concentration of MnTBAP was 42 mg/L and 80 ⁇ g/g protein, respectively. The elimination half-lives of MnTBAP from the serum and lung were identical at 9.5 hours.
  • MnTBAP does not accumulate in the lung; and 2) a twice a day dosing regimen based on its half-life of 9.5 hours.
  • mice were randomized into 4 groups using a two by two contingency table where two groups received either saline or bleomycin (3.5 U/kg body weight) by intratracheal instillation. Two groups also received either saline or MnTBAP (5 mg/kg body weight) by ip injection twice daily for 14 days. The groups that received bleomycin lost significantly more weight than vehicle controls over 14 days with a maximum average loss of 20% of their initial body weight (FIG. 8). MnTBAP treatment did not cause weight loss as compared to the saline control group. The group of mice that received both bleomycin and MnTBAP had less weight loss than the bleomycin group from day 5 to 14 with a maximum average loss of 10%.
  • Bleomycin given by intratracheal instillation produces a marked airway and alveolar fibrotic response (Evans et al, Am Rev. Respir. Dis. 125(l):89-94 (1982)).
  • Mice were assessed for changes in airway function by measuring a marker, enhanced pause (P ENH ), of airway narrowing using non-invasive whole body barometric plethysmography.
  • Intratracheal bleomycin treatment produced a 3-fold increase in the P ENH index of airway constriction after 14 days (FIG. 9A).
  • MnTBAP treatment alone did not affect the P ENH marker, but caused a 30% decrease in airway constriction produced by bleomycin treatment.
  • Lung fibrosis was also assessed by measuring hydroxyproline content in the lung as an index of collagen accumulation.
  • Bleomycin treatment produced a 2-fold increase in hydroxyproline content of the lung after 14 days (FIG. 9B).
  • MnTBAP treatment had little effect on hydroxyproline content of the lung, but produced a 23% decrease in hydroxyproline content caused by bleomycin treatment.
  • Increases in both P ENH and hydroxyproline content correlated well with fibrotic changes seen by histopathology assessment.
  • Lung sections were semi-quantitatively assessed for fibrotic response on a scale of 0-8 with a score of one representing a normal lung and a score of 8 representing a very severe fibrotic lung. Lung sections were randomized and scored blinded. Bleomycin treatment produced a 2-fold increase in the pathology score as compared to the control group (FIG. 11). MnTBAP treatment had no effect on the pathology score, but attenuated the bleomycin pathology score by 28%. These results closely support the physiologic and biochemical indices where bleomycin produced about a 2-fold increase in the various indices and MnTBAP attenuated these increases by roughly 30%.
  • AEOL 10113 was tested (6 mg/kg/day for 5 days beginning on the day of irradiation) in a rat model of radiation-induced lung injury as assessed by breathing rate (animals with lung injury have a more rapid respiration rate), and chemical and microscopic measures of fibrosis. During the follow-up period of 6 months, 4 of the 9 rats receiving radiation only developed severe respiratory distress and were euthanized. In the group of rats treated with radiation plus AEOL 10113, only 1 of the 9 rats developed respiratory distress and was euthanized. Breathing rate data were analyzed on a last observation carried forward (LOCF) data set, in which the last observation for rats euthanized due to respiratory distress was imputed to subsequent weeks.
  • LOCF last observation carried forward
  • FIG. 13A shows there were no differences in the hydroxyproline content of the right upper lobe between the control group (no radiation, no AEOL 10113) of animals and those that received AEOL 10113 without radiation.
  • a significant increase in hydroxyproline content per gram of dry or wet lung was observed in animals receiving radiation only (28 Gy single dose).
  • administration of AEOL 10113 before and for 4 days after radiation resulted in a significant reduction (p ⁇ 0.05) in hydroxyproline content in both wet and dry upper right lobe.
  • FIG. 13B Radiation-induced lung fibrosis was also assessed using histopathology (FIG. 13B). Lungs were fixed in 10% neutral buffered formalin. Five-Micron thick sections were stained with hematoxylin and eosin or Masson trichrome and examined microscopically. Slides were systematically scanned in a microscope using a ⁇ 10 objective. Each successive field was individually assessed for severity of interstitial fibrosis and allotted a score of between 0 and 8. These data indicate AEOL 10113 also reduced radiation-induced lung fibrosis.
  • Non-tumor cell lines rat lung epithelial cells, L2; bovine endothelial cells, CPA-47
  • tumor cell line human adenocarcinoma lung cells, A549
  • FIG. 16 Cells were plated in 24 well plates at 10,000 cells per well in the presence or absence of 100 ⁇ M MnTBAP, MnTM-4-PyP and their zinc analogs for 48 hours. None of the compounds produced cytotoxicity (as measured by LDH release) at this concentration.
  • Manganic porphyrins selectively inhibited tumor cell proliferation up to 50% compared to tumor cell growth without manganic porphyrins. In contrast, manganic porphyrins had no suppressive effects on non-tumor cell growth. This finding supports the in vivo tumor transplantation studies in that manganic porphyrins can selectively inhibit tumor cell proliferation and may be efficient chemotherapeutic agents.
  • non-tumor cell lines rat lung epithelial cells, L2; bovine endothelial cells, CPA-47
  • tumor cell line human adenocarcinoma lung cells, A549
  • manganic porphyrins protected non-tumor cells against the cytotoxic effects of paraquat.
  • the manganic porphyrins may provide selective potentiation of the other redox cycling cytotoxic chemotherapeutic such as bleomycin and adriamycin in tumor cells while protecting non-tumor cells against the damaging effects of these cytotoxic agents (see FIG. 17).
  • Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of drug and radiation therapy for cancer.
  • the disorder is characterized by breakdown of the oral mucosa that results in the formation of ulcerative lesions.
  • the ulcerations that accompany mucositis are frequent portals of entry for indigenous oral bacteria often leading to sepsis or bacteremia.
  • Mucositis occurs to some degree in more than one third of patients receiving anti-neoplastic drug therapy. The frequency and severity are significantly greater among patients who are treated with induction therapy for leukemia or with many of the conditioning regimens for bone marrow transplant.
  • moderate to severe mucositis is not unusual in more than three-quarters of patients.
  • Moderate to severe mucositis occurs in virtually all patients who receive radiation therapy for tumors of the head and neck and typically begins with cumulative exposures of 15 Gy and then worsens as total doses of 60 Gy or more are reached.
  • Standard therapy for mucositis is predominantly palliative, including application of topical analgesics such as lidocaine and/or systemic administration of narcotics and antibiotics.
  • topical analgesics such as lidocaine
  • systemic administration of narcotics and antibiotics Currently, there is no approved treatment for mucositis.
  • this scale is defined as follows: Score: Description: 0 Pouch completely healthy. No erythema or vasodilation 1 Light to severe erythema and vasodilation. No erosion of mucosa 2 Severe erythema and vasodilation. Erosion of superficial aspects of mucosa leaving denuded areas. Decreased stippling of mucosa. 3 Formation of off-white ulcers in one or more places. Ulcers may have a yellow/gray due to pseudomembrane. Cumulative size of ulcers should equal about 1 ⁇ 4 of the pouch. Severe erythema and vasodilation.
  • a score of 1-2 is considered to represent a mild stage of the disease, whereas a score of 3-5 is considered to indicate moderate to severe mucositis.
  • FIG. 18 illustrates the distribution of scores over time in the experiment. From these data it appears that the effect of 10150 occurs in the initiation of mucositis, reducing the incidence of ulcers at peak time, approximately day 14.
  • FIG. 19 displays the effect on 10150 on the percent of days with scores ⁇ 3 (i.e. severe mucositis).

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