ES2384208T3 - Composiciones medicinales para el tratatamiento intravesical del cáncer de vejiga. - Google Patents

Composiciones medicinales para el tratatamiento intravesical del cáncer de vejiga. Download PDF

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ES2384208T3
ES2384208T3 ES06077149T ES06077149T ES2384208T3 ES 2384208 T3 ES2384208 T3 ES 2384208T3 ES 06077149 T ES06077149 T ES 06077149T ES 06077149 T ES06077149 T ES 06077149T ES 2384208 T3 ES2384208 T3 ES 2384208T3
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vol
cancer
mmc
bioreductive
bladder
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Bastiaan Nuijen
Ernie Pfadenhauer
Jos F. Beijen
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Spectrum Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Organic Chemistry (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Una formulación anticancerígena que comprende: a) (5-(1-aziridinyl)-3-(hidroximetil)-2-[(E)-3-hidroxiprop-1-enil]-1-metil-1H-indol-4,7-dione] (E09); y b) glicol de propileno.

Description

ANTECEDENTES DE LA INVENCION
[0001] El cáncer de vejiga representa aproximadamente el 2% de todos los cánceres malignos y es el quinto y el décimo cáncer más común en hombres y mujeres, respectivamente. La Sociedad Americana del Cáncer estimó que 54.500 nuevos casos y 11.700 muertes se habrían producido en 1997. Los cánceres superficiales de vejiga (pTa, pT1 y CIS) responden del 70 -80% de la primera realización del cáncer. El control del cáncer superficial de vejiga puede conseguirse mediante cirugía de resección endoscópica seguida a menudo por un tratamiento de quimioterapia intravesical auxiliar o inmunoterapia con el objetivo de erradicar las células tumorales celulares restantes y evitar la recurrencia del tumor (Herr HW (1987) Intravesical therapy-a critical review. Urol Clin N Am 14: 399-404). Ambos anti-neoplásicos (Mitomicina C [MMC], epirubicina y tioTHEPA) y la inmunoterapia (BCG), administrados intravesicalmente son eficaces en la reducción de la tasa de recidiva del tumor, aunque no está claro si se evita la progresión de la enfermedad a tumores invasivos del músculo (Newling D (1990) Terapia Intravesical en el control del carcinoma de células superficiales transicionales de la vejiga, experiencia del grupo EORTC GU, Br J Cancer 61:497-499; Oostenink et al. (1993) Un ensayo aleatorio prospectivo del Grupo de la Organización Europea para Investigación y Tratamiento del Cancer Genitourinario comparando la resección transuretral seguida de una instilación única de epirubicina o agua en una sola etapa Ta, carcinoma papilar T1 de la vejiga. J Urol 149:749-752). Esta observación junto con el hecho de que la mortalidad por cáncer de vejiga sigue siendo alta subraya la necesidad de desarrollar más agentes terapéuticos eficaces (Oosterlink et al. 1993).
[0002] Un agente terapéutico tal es el MMC que pertenece a una clase de compuestos conocidos como medicamentos bioreductores (Workman 1994). MMC representa uno de los agentes antineoplásicos utilizados para tratar el cáncer superficial de vejiga (Maffezzini et al, 1996, Tolley et al. 1996). MMC es activado a una especie citotóxica por reductasas celulares aunque el papel de las enzimas reductasas específicas implicadas en la activación bioreductiva sigue siendo poco definido y controvertido (Cummings et al, 1998a). Esto es particularmente cierto para la enzima NQ01 (NAD (P) H: Quinona oxidorreductasa, EC 1.6.99.2), que es una flavoproteína citosólica que cataliza la reducción de dos electrones de varios compuestos a base de quinona utilizando NADH o NADPH como donantes de electrones (Schlager y Powis. 1988, Siegel et al, 1990). El compuesto estructuralmente relacionado E09 (5 - (1-aziridinilo) -3 - (hidroximetil) -2 [(E)-3-hidroxiprop-] 1-enil-1-metil-1H-indol-4] ,7-diona, es sin embargo un sustrato mucho mejor para NQO1 que MMC (Walton et al 1991), y existe una buena correlación entre la actividad NQO1 y la quimiosensibilidad in vitro en condiciones aeróbicas (Robertson et al, 1994, Fitzsimmons et al, 1996, Smitkamp-Wilms et al, 1994). Bajo condiciones de hipoxia sin embargo, las propiedades de E09 son muy diferentes con poca o ninguna potenciación de la toxicidad de E09 observada en células ricas en NQO1 (Plumb y Workman, 1994). En las líneas celulares deficientes en NQ01 sin embargo, se han encontrado grandes proporciones de citotoxicidad hipóxica (Workman, 1994). Por lo tanto, E09 tiene el potencial para aprovechar la fracción aeróbica de los tumores ricos en NQ01 o la fracción aeróbica de los tumores deficientes en NQO1 (Workman, 1994).
[0003] E09 ha sido evaluado clínicamente pero a pesar de los informes de tres remisiones parciales en los ensayos clínicos de fase, ninguna actividad fue observada en contra de NSCLC, cáncer gástrico, de mama, de páncreas y el cáncer de colon en posteriores estudios de fase II (Schellens et al, 1994, Dirix et al, 1996). Estos hallazgos son especialmente decepcionantes a la vista de los estudios preclínicos (Hendriks et al, 1993) junto con los informes que varios tipos de tumores tienen niveles elevados de NQO1 (Malkinson et al, 1992, Smitkamp-al de Wilms y otros, 1995, Siegel et al, 1998). Varias explicaciones posibles han sido propuestas para explicar la falta de eficacia clínica del E09 (Connors, 1996, Phillips et al, 1998). Estudios recientes han demostrado que el fallo de E09 en la clínica puede no ser debido a las malas interacciones farmacodinámicas pero puede ser el resultado de la mala administración de fármacos a los tumores (Phillips et al, 1998). La eliminación rápida en plasma de la E09 (t1/2= 10 min en los seres humanos) junto con la escasa penetración a través de capas multicelulares sugiere que el E09 no penetrará más de unas pocas micras de un vaso sanguíneo dentro de su vida útil farmacocinética (Schellens et al, 1994, Phillips y otros, 1998). La administración intratumoral de E09 a los tumores ricos y deficientes en NQO1 produjo importantes retrasos de crecimiento (aunque una distinción entre el daño a la fracción aeróbica o hipóxica no ha sido determinada), sugiriendo que si E09 puede ser administrado para los tumores, se pueden conseguir efectos terapéuticos (Cummings et al, 1998b). Si bien estas características indeseables son un serio revés para el tratamiento de la enfermedad sistémica, paradójicamente, pueden ser ventajosas para el tratamiento de cánceres que se presentan en un tercer compartimiento, como el cáncer superficial de vejiga. En este escenario, la administración del medicamento no es problemática por la ruta intravesical y la penetración de la E09 en el tejido avascular puede incrementarse por el mantenimiento terapéutico de concentraciones importantes de medicamentos dentro de la vejiga (usando un periodo de instilación de una hora por ejemplo). Mientras que este método de instilación E09 dentro de la vejiga puede ser útil, todavía sigue siendo una necesidad de vehículos de administración del medicamento capaces de entregar una cantidad eficaz de E09 dentro de la vejiga.
[0004] JD de Vries et al (Int J Farmacia, 100 (1993) 181-188) investigaron la estabilidad química del E09 utilizando un ensayo en fase inversa indicador de estabilidad de HPLC con detecciones UV y espectrofotometría UV. La cinética de degradación del E09 fue estudiada como una función de pH, composición del tampón, fuerza iónica y temperatura.
[0005] JD Jonkman-de Vries et al (Quimioterapia del cáncer Pharmacol (1994) 34:416-422) informó de un estudio para diseñar una forma de dosificación parenteral estable de E09. El estudio investigó la atomización de soluciones acuosas de E09.
[0006] Choudry et al (Br J Cancer (2001) 85 (8), 1137-1146) describe composiciones para el tratamiento de cáncer de vejiga, estas composiciones incluyen E09. Este documento estudia la relación entre la actividad NQO1 en el tejido tumoral y selectividad de E09. Además, Choudry at al enseña que la entrega de E09 en un vehículo acídico resulta en una mayor actividad dentro de la vejiga con cualquier fármaco absorbido en el torrente sanguíneo volviéndose relativamente inactivo debido al aumento en el pH. Sin embargo, este documento no discute métodos para la estabilización de una composición E09 reconstituida.
BREVE RESUMEN DE LA INVENCION
[0007] De acuerdo con la presente invención, se provee una formulación contra el cáncer tal como se define en la Reivindicación 1, comprendiendo EO9 y glicol de propileno.
[0008] De acuerdo con la presente invención, la composición de la presente invención comprende E09 y un agente de recubrimiento que es glicol de propileno. El agente de recubrimiento permite una mejor adherencia de la composición a la pared de la vejiga. En consecuencia, la composición y, en particular, el E09 contacta y puede ser capaz de penetrar en el tejido avascular que comprende por un tiempo suficiente para tratar el cáncer de vejiga.
DESCRIPCION DETALLADA DE LA INVENCION
[0009] Las realizaciones de la presente invención están dirigidas a composiciones para el tratamiento de cáncer de vejiga vía instilación intravesical. Se divulga aquí una composición que comprende5-(1-aziridinilo)-3-(hidroximetil)-2-[(E)-3-hidroxiprop-1-enil]-1-metil-1H-indol-4,7-dion a (E09) y un vehículo de formulación. Los vehículos de formulación son disolventes que mejoran la solubilidad y estabilidad de EO9.
[0010] Según una realización ejemplar, la formulación anti-cáncer puede ser preparada usando un vehículo reconstituyente que consta de 2% de bicarbonato de sodio, 0,02% edetato disódico y glicol de propileno: agua (60:40 V/V). Este vehículo de reconstitución disuelve la composición liofilizada y produce una solución estable para administración de hasta 24 horas. Adicionalmente, el vehículo de reconstitución proporciona una ampolla teniendo un volumen extraíble de 5 ml de E09 reconstituído comprendiendo glicol de propileno/agua/bicarbonato de sodio/edetato de sodio 60/40/2/0.02% vlv/p/p.
Choudry GA, Hamilton Stewart PA, Double JA, Krul MRL, Naylor B, Flannigan GM, Shah TK, Brun JE y Phillips RM (2001); A novel strategy for NQO1 (NAD(P)H: quinine oxidoreductase, EC 1.6.99.2) mediated therapy of bladder cancer based on the pharmacological properties of E09. Br J Cancer 85 (8) 1137-1146.
Connors TA (1996) Bioreductive agents, hypoxic cells and therapy. Eur J Cancer 32A: 1833-1834.
Cummings J, Spanswick VJ, Tomaz M and Smyth JF (1998a) Enzymology of MMC metabolic activation in tumor tissue. Implications for enzyme directed bioreductive drug development Biochem Pharmacol 56: 405-414.
Cummings J, Spanswick VJ, Gardiner J, Ritchie A and Smyth, IF (1998b) Pharmacological and biochemical determinants of the antitumour activity of the indoloquinone E09. Biochem Pharmacol 55: 253-260.
Dirix LY, Tonnesen F, Cassidy J, Epelbaum R, Huinink WWT, Pavlidis N, Sorio R, Gamucci T, Wolff I, Tevelde A, Lan J, and Verweij J (1996) E09 phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the early clinical studies group. Eur J Cancer 32A: 2019-2022.
Fitzsimmons S A, Workman P, Grever M, Paull K, Camalier R and Lewis AD (1996) Reductase enzyme expression across the National Cancer Institute tumor cell line panel: Correlation with sensitivity to MMC and E09. J Natl Cancer Inst 88: 259-269 Gutierrez PL (1989) Mechanism of bioreductive alkylation. The example of diazaquinone (AZQ. Free Radical Bio Med 6: 405-445.
Hendriks HR. Piazo PE, Berger DP, Kooistra KL, Bibby MC, Boven E, Dreef-Van Der Meulen HC, Henrar-REC, Fiebig HH, Double JA, Homstra HW, Pinedo HM, Workman P and Swartsmann G (1993) E09: A novel bioreductive alkylating indoloquinone with preferential solid tumor activity and lack of bone marrow toxicity in preclinical models. Eur J Cancer 29A: 897-906.
Herr HW (1987) Intravesical therapy - a critical review. Urology Clinics of N America 14: 399-404.
Maffezzini M, Simonata A, Zanon M, Raber M and Carmig ani G (1996) Up-front chemotherapy for low stage low grade recurrent bladder cancer. J Urol 155; 91-93 . Malkinson AM, Siegel D, Forrest GL, Gazdar AF, Oie HK, Chan DC, Bunn PA, Mabry M, Dykes DJ, Harrison SD and Ross D (1992) Elevated NQO1 activity and messenger RNA content in human non small cell lung carcinoma - Relationship to the response of lung tumor xenografts to MMC. Cancer Res 52: 4752-4757.
Newling D (1990) Intravesical therapy in the management of superficial transitional cell carcinoma of the bladder: the experience of the EORTC GU group. Br J Cancer 61: 497-499.
Oosterlink W, Kurth KH, Schr6der F, Bultinck J, Hammond B, Sylvester R, and members of the European Organisation for Research and Treatment of Cancer Genitourinary
Phillips RM, Loadman PM and Cronin BP (1998) Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumors. Br J Cancer 77: 2112-2119.
Plumb JA and Workman P (1994) Unusually marked hypoxic sensitisation to indoloquinone E09 and MMC in a human colon tumor cell line that lacks NQOI activity. Int J Cancer 56: 134-139.
Robertson N, Haigh A, Adams GE and Stratford U (1994) Factors affecting sensitivity to E09 in rodent and human tumor cells in vitro: NQO1 activity and hypoxia. Eur J Cancer 30A: 1013-1019.
Schellens JHM, Planting AST, Van Acker BAC, Loos WJ, De Boer-Dennert M, Van Der Burg MEL, Koier I, Krediet RT, Stoter G and Verweij J (1994) Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09. J Natl Cancer Inst 86: 906-912.
Schlager JJ and Powis G (1988) MMC is not metabolized by but is an inhibitor of human kidney NAD(P) H:(quinone acceptor) oxidoreductase. Cancer Chemother Pharmacol 22: 126-130.
Siegel D, Franklin WA and Ross D (1998) Immunohistochemical detection of NAD(P)H:Quinone oxidoreductase in human lung and lung tumors. Clin Cancer Res 4: 2065-2070.
Smitkamp-Wilms E, Peters GJ, Pinedo HM, Van Arkotte J and Giaccone G (1994) Chemosensitivity to the indoloquinone E09 is correlated with NQ01 activity and gene expression. Biochem Pharmacol 47: 1325-1332.
Smitskamp-Wlms E, Giaccone G, Pinedo HM, Van Der Laan BFAM and Peters GJ (1995) NQO1 activity in normal and neoplastic human tissues: An indicator of sensitivity to bioreductive agents ?. Br J Cancer 72: 917-921.
Tolley DA, Parmar MKB, Grigor KM, Lallemand G and the Medical Research Council superficial bladder cancer working party (1996) The effect of intravesical MMC on recurrence of newly diagnosed superficial bladder cancer A further report with 7 years of followup. J Urol 155: 1233-1238.
Walton MI, Smith PJ and Workman P (1991) The role of NAD(P)H:quinone reductase (EC 1.6.99.2, NQ01) in the reductive bioactivation of the novel indoloquinone antitumour agent E09. CancerCommun 3: 199-206.
Workman P (1994) Enzyme directed bioreductive drug development revisited: A commentary on recent progress and future prospects with emphasis on quinone anticancer drugs and quinone metabolizing enzymes, particularly NQO1. Oncol Res 6: 461-475.

Claims (2)

  1. Reivindicaciones
    1.
    Una formulación anticancerígena que comprende: a) (5-(1-aziridinyl)-3-(hidroximetil)-2-[(E)-3-hidroxiprop-1-enil]-1-metil-1H-indol-4,7-dione] (E09); y b) glicol de propileno.
  2. 2.
    Una formulación anticancerígena según la reivindicación 1 que comprende una dosis unitaria de 8 mg de E09.
    REFERENCIAS CITADAS EN LA DESCRIPCION Esta lista de referencias citadas por el solicitante es solamente para conveniencia del lector. No forman parte del documento de la patente europea. Aún cuando la compilación de referencias se ha hecho con sumo cuidado, errores u omisiones no pueden ser excluidas y la EPO declina toda responsabilidad en este aspecto.
    Bibliografía citada en la descripción que no forma parte de la patente.
    •
    Herr HW. Intravesical therapy-a critical review. Urol Clin N Am, 1987, vol. 14, 399-404 [0001]
    •
    Newling D. Intravesical therapy in the management of superficial transitional cell carcinoma of the bladder the experience of the EORTC GU group. Br J Cancer,1990, vol. 61, 497-499 [0001]
    •
    Oostenink et al. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol, 1993, vol. 149, 749-752 [0001]
    •
    J D de Vries et al. Int J Pharmaceutics, 1993, vol. 100, 181-188 [0004]
    •
    J D Jonkman-de Vries et al. Cancer Chemother Pharmacol, 1994, vol. 34, 416-422 [0005]
    •
    Choudry et al. Br J Cancer, 2001, vol. 85 (8), 1137-1146 [0006]
    •
    Choudry GA ; Hamilton Stewart PA ; Double JA ; Krul MRL ; Naylor B ; Flannigan GM ; Shah TK ; Brun JE ; Phillips RM. A novel strategy for NQO1 (NAD(P)H: quinine oxidoreductase, EC 1.6.99.2) mediated therapy of bladder cancer based on the pharmacological properties of E09. Br J Cancer, 2001, vol. 85 (8), 1137-1146 [0010]
    •
    Connors TA. Bioreductive agents, hypoxic cells and therapy. Eur J Cancer, 1996, vol. 32A, 1833-1834 [0010]
    •
    Cummings J ; Spanswick VJ ; Tomaz M ; Smyth JF. Enzymology of MMC metabolic activation in tumor tissue. Implications for enzyme directed bioreductive drug development. Biochem Pharmacol, 1998, vol. 56, 405-414 [0010]
    •
    Cummings J ; Spanswick VJ ; Gardiner J ; Ritchie A ; Smyth, IF. Pharmacological and biochemical determinants of the antitumour activity of the indoloquinone E09. Biochem Pharmacol, 1998, vol. 55, 253-260 [0010]
    •
    Dirix LY ; Tonnesen F ; Cassidy J ; Epelbaum R ; Huinink WWT ; Pavlidis N ; Sorio R ; Gamucci T ; Wolff I ; Tevelde A. E09 phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the early clinical studies group. Eur J Cancer, 1996, vol. 32A, 2019-2022 [0010]
    •
    Fitzsimmons S A ; Workman P ; Grever M ; Paull K ; Camalier R ; Lewis AD. Reductase enzyme expression across the National Cancer Institute tumor cell line panel: Correlation with sensitivity to MMC and E09. J Natl Cancer Inst, 1996, vol. 88, 259-269 [0010]
    •
    Gutierrez PL. Mechanism of bioreductive alkylation. The example of diazaquinone (AZQ. Free Radical Bio Med, 1989, vol. 6, 405-445 [0010]
    •
    Hendriks HR ; Piazo PE ; Berger DP ; Kooistra KL ; Bibby MC ; Boven E ; Dreef-Van Der Meulen
    HC ; Henrar-REC ; Fiebig HH ; Double JA. E09: A novel bioreductive alkylating indoloquinone with preferential solid tumor activity and lack of bone marrow toxicity in preclinical models. Eur J Cancer, 1993, vol. 29A, 897-906 [0010]
    •
    Herr HW. Intravesical therapy - a critical review. Urology Clinics of N America, 1987, vol. 14, 399-404 [0010]
    •
    Maffezzini M ; Simonata A ; Zanon M ; Raber M ; Carmig ani G. Up-front chemotherapy for low stage low grade recurrent bladder cancer. J Urol, 1996, vol. 155, 91-93 [0010]
    •
    Malkinson AM ; Siegel D ; Forrest GL ; Gazdar AF ; Oie HK ; Chan DC ; Bunn PA ; Mabry M ; Dykes DJ ; Harrison SD. Elevated NQO1 activity and messenger RNA content in human non small cell lung carcinoma - Relationship to the response of lung tumor xenografts to MMC. Cancer Res, 1992, vol. 52, 4752-4757 [0010]
    •
    Newling D. Intravesical therapy in the management of superficial transitional cell carcinoma of the bladder: the experience of the EORTC GU group. Br J Cancer, 1990, vol. 61, 497-499 0010]
    •
    Phillips RM ; Loadman PM ; Cronin BP. Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumors. Br J Cancer,1998, vol. 77, 2112-2119 [0010]
    •
    Plumb JA ; Workman P. Unusually marked hypoxic sensitisation to indoloquinone E09 and MMC in a human colon tumor cell line that lacks NQOI activity. Int J Cancer, 1994, vol. 56, 134-139 [0010]
    •
    Robertson N ; Haigh A ; Adams GE ; Stratford U.Factors affecting sensitivity to E09 in rodent and human tumor cells in vitro: NQO1 activity and hypoxia. Eur J Cancer, 1994, vol. 30A, 1013-1019 [0010]
    •
    Schellens JHM ; Planting AST ; Van Acker BAC ; Loos WJ ; De Boer-Dennert M ; Van Der Burg MEL ; Koier I ; Krediet RT ; Stoter G ; Verweij J. Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09. J Natl Cancer Inst, 1994, vol. 86, 906-912 [0010]
    •
    Schlager JJ ; Powis G. MMC is not metabolised by but is an inhibitor of human kidney NAD(P)H:(quinine acceptor) oxidoreductase. Cancer Chemother Pharmacol,1988, vol. 22, 126-130 [0010]
    •
    Siegel D ; Franklin WA ; Ross D. Immunohistochemical detection of NAD(P)H:Quinone oxidoreductase in human lung and lung tumors. Clin Cancer Res, 1998, vol. 4, 2065-2070 0010]
    •
    Smitkamp-Wilms E ; Peters GJ ; Pinedo HM ; Van Arkotte J ; Giaccone G. Chemosensitivity to the indoloquinone E09 is correlated with NQ01 activity and gene expression. Biochem Pharmacol, 1994, vol. 47,1325-1332 [0010]
    •
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