Drjschumann.de

________________________________________________________________________________MYLERAN Einleitung
experimentelle Zwecke und für klinische Studienparenterale Darreichungsformen entwickelt wurden.
1953 berichteten erstmals Haddow et al. und Galtonüber die Wirksamkeit des Busulfan in der Behandlung Pharmakodynamik
der chronisch myeloischen Leukämie (CML). Seitdem hat es seine Position in der Therapie der CML gefestigt, auch wenn es primär nicht kurativwirkt, sondern zum subjektiven Wohlbefinden der Chemisch gesehen, ist Busulfan das 1,4-Bis- Patienten durch Reduzierung der erhöhten Zellzahl (methansulfonyloxi)-butan mit einer Summenformel und Beseitigung der Sekundärsymptomatik beiträgt.
von C6H14O6S2. Es hat eine molare Masse von 246,3.
Als nicht Zellzyklusspezifisches bifunktionelles Neben der INN-Bezeichnung, Busulfan, wird dieses Zytostatikum auch unter den Namen, Myelosan, proliferierende Zellen, besonders auf die der Sulfabutin, Misbulban oder Mitosan geführt. 12 Granulopoese im Knochen-mark. Speziell beiniedrigen Dosen wird eine gewisse Selektivität Die Wirkung des Busulfan als Alkylgruppen- gegenüber der granulozytären Zellinie sichtbar, übertragende Substanz ist Konzentrationsabhängig während bei höheren Busulfan-Dosen auch und unterliegt dem nukleophilen Substitutionstyp 2 Thrombozyten, Lymphozyten und die erythrozytäre Zellinie supprimiert werden. (Buggia et al. 1994) 3 - 7 demzufolge nicht nur von der Busulfan-Konzentration Neben der CML fand Busulfan besonders in den 70er selbst, sondern auch auf die Konzentration der Jahren Eingang in die Behandlung der Polycythaemia Nukleophilen abhängig, die durch Busulfan alkyliert vera und der essentiellen Thrombozytämie. (Ernst et werden sollen. Auch andere Bisulfonate mit den al. 1971; Brodsky et al. 1977) 8,9; (EORTC-Studie unterschiedlichsten Alkylgruppen zwischen den 1981; Levis und Szur, 1974) 10,11 beiden funktionellen Gruppen wurden auf ihrezytostatische Aktivität hin untersucht. Keine 1983 eröffnete eine Publikation von Santos et al. ein Verbindung jedoch erreichte die Effizienz des neues Einsatzgebiet für Busulfan. In Kombination mit Busulfan mit seinen 4 Methylengruppen zwischen den Cyclophosphamid hatte sich Busulfan in der Methylsulfonaten im bezug auf die Hemmung Konditionierungsbehandlung von Patienten, die sich einer Knochenmarktransplantation im Rahmen einerAML-Therapie unterzogen hatten, als sehr effizient Dunn postulierte 1974 zwar für das Busulfan einen erwiesen. 4 Dieser Studie folgten weitere, in denen anderen Wirkungsmechanismus als für die Stickstoff- hochdosiertes Busulfan mit Cyclophosphamid oder Lostverbindungen, jedoch ist dieses nicht einsehbar, anderen Substanzen einschließlich einer Radiatio da Busulfan intrazellulär - vergleichbar den Stickstoff- kombiniert wurde. So hat es sich seitdem in der Konditionierungstherapie zur autologen bzw.
seiner Methylsulfonatgruppe alkyliert. Dieses können allogenen Knochenmarktransplantation im Rahmen sowohl Proteine wie auch die Nukleinsäuren in der der Behandlung von Leukämien, soliden Tumoren und Hämoglobinopathien etabliert und bewährt. 3 Auchwenn die Konditionierungsbehandlung mit Busulfan Die Aggressivität als Alkylgruppen-übertragendes bisher nicht zu den zugelassenen Indikationen zählt, Zytostatikum dürfte sicherlich weit unter der der wird dieses Alkylanz - offensichtlich wegen seiner Stickstoff-Lostverbindungen einschließlich des vorhersehbaren sonstigen toxischen Risiken Chlorambucil und Melphalan liegen. Dennoch ist davon auszugehen, daß Thiol- oder Aminogruppen alsintrazelluläre Angriffspunkte für Busulfanfungieren. Sulfhydryl-Gruppen betrifft, dürfte es sich bei dieserForm der Alkylierung eher um einen Katabolismusdes Zytostatikums, Busulfan, handeln, da sieirreversibel zu harnpflichtigen Thiophen-verbindungen führt. (Roberts et al. 1959) 13,14 Als bifunktionelles Alkylanz substituiert Busulfanzunächst den stark basischen Stickstoff in der Position Abb. 1 : Strukturformel des Busulfan [1,4-Bis-(methylsulfonyloxi)-
7 des Guanins in der DNS und setzt dort den butan]. * = Positionen, an denen das Molekül aufgespalten wird.
Busulfan wird als Arzneimittel unter dem Ausgangspunkt für eine weitere nukleophile Handelsnamen, Myleran, ausschließlich in Form von Substitutionen an einem zweiten Guaninmolekül.
Tabletten zu 0,5 und 2 mg vertrieben, auch wenn für Durch die Bifunktionalität des Busulfan, ausgehend ________________________________________________________________________________MYLERAN von der Quaternierung des N-7-Stickstoffs kann die Die Ursachen für die Zytotoxizität von Busulfan Vernetzung innerhalb des gleichen DNS-Stranges gegenüber Tumorzellen sind vielfältig. Dabei spielt oder zu dem Nachbarstrang hin erfolgen, was die Brückenbildung zu den Guaninbasen der DNS entweder eine intrahelikale oder interhelikale sicherlich die wichtigste Rolle. Ob dieser Vorgang kovalente Vernetzung der DNS-Stränge nach sich allerdings die Hauptwirkung repräsentiert, kann nicht zieht. 15,16 Brookes und Lawley (1961 und 1965) uneingeschränkt bejaht werden, da nach Tong et al. postulierten für die Kreuzvernetzung der DNS durch Busulfan eine stufenweise ablaufenden nukleophile Substitution am Guanin, die von Tong et al. (1980)durch den Nachweis des 1,4-Di-(7-guanosyl)-butan Auf die Möglichkeit, durch Busulfan Bindungen bzw. des 1,4-Di-(7-guanyl)-butan belegt werden zwischen der DNS und den DNS-assoziierten Proteinen zu induzieren, wiesen Lee und Zbinden(1979) hin. Sie konnten allerdings keinen eindeutigenBeweis dafür erbringen, daß Busulfan auch solcheDNS-Proteinverknüpfungen macht. Alexander und Stacey in der Veresterung der Phosphatbrücken der DNS einen weiteren, wichtigenbiochemischen Angriffspunkt für Busulfan, der einSistieren des Zellzyklus nach sich ziehen könnte. 21 Bezüglich der verschiedenen Phasen eines Zellzyklusund der Erreichung eines optimalen zytostatischen Effekts durch Busulfan, gibt es divergierende Abb. 2 : Vernetzung der DNS durch kovalente Bindungen am N-7
Aussagen. Während Dunn (1974) Zellen in der G0- Phase, wie Megakaryozyten und enddifferenzierteZellen, als ideal für den Busulfan-Effekt ansah 22, Tong und Ludlum gelangen allerdings nicht der geben in-vitro-Studien Hinweise darauf, daß Zellen in Nachweis, ob die Bisguanylverbindung aus einer Inter- oder Intra-Strangverknüpfung resultierte. In empfindlich auf die Busulfan-Gabe reagieren und den einem von Lee und Zbinden fehlgeschlagenen Versuch, eine bestimmte DNS-Fraktion aus Zellen 1982) 73 Buggia et al. sehen deshalb in den schnell von mit Busulfan behandelten Ratten zu eluieren, proliferierenden Geweben, worunter besonders die sehen Bishop und Wassom den Beleg für eine vom granulozytäre Zellreihe des Knochenmarks fällt, die Busulfan bevorzugte Alkylierung des Einzelstranges, bevorzugten Angriffspunkte für Busulfan. 3 nicht aber für eine Interstrang-DNS-Verknüpfung odereine DNS-Nukleoprotein-Vernetzung. 16,19,12 Zytotoxizität
Mit einer Substitution des N-7-Stickstoffs im Guaninist eine Instabilität des Imidazolringes verbunden, die Busulfan entfaltet seine toxische Wirkung auf alle mit einer Öffnung des Ringsystems verbunden sein menschlichen und tierischen Gewebe, maligne wie kann. Ist ein bestimmtes Maß an Vernetzung erreicht, auch gesunde. Als Folge können Dysplasien erlaubt die so veränderte DNS keine reguläre entstehen, von denen die bekannteste die Busulfan- Transkription und indirekt auch dadurch keine Lunge ist, die bereits in den 60er Jahren nach Translation mehr, so daß eine Zellvermehrung und Einführung von Busulfan in die Therapie der CML als eine Proteinsynthese nachhaltig gestört, ja sogar unerwünschte Arzneimittelwirkung erkannt wurde.
(Meschan et al. 1973; Koss et al. 1965; Leake et al.
1963) 23,24,25 Ferner sind zytologische Veränderungen Voraussetzung für die Entfaltung einer solchen Wirkung ist eine Penetration des Zytostatikums in die Gastrointestinaltraktes und der neuronalen Gewebe Zelle, für die nach dem jetzigen Erkenntnisstand weder ein Rezeptor noch ein aktiver Transport Offensichtlich wirkt Busulfan nur unwesentlich auf diskutiert werden. Die geringe Löslichkeit in Wasser das lymphatische Gewebe und auf Leberzellen von und hohe Lipophilie ermöglichen nach Wilkinson und Nagern, obwohl bei Mäusen Lymphknotenatrophien Turner dem Busulfan eine gute Zellpenetration, die zu beobachtet wurden. Seiner gonadotoxischen Wirkung einer erhöhten Zellpermeabilität verbunden mit einer verdankt in einigen Ländern Busulfan den Instabilität der Zellwand und somit zu einer Störung zweifelhaften Einsatz bei der Regulierung von des Zellwachstums verschiedener maligner Klone geführt hat. In der unterschiedlichen Permeabilität dieser Zellen gegenüber Busulfan sehen die Autoreneinen Grund für die relative Selektivität dieses Zytostatikums gegenüber Granulozyten und ________________________________________________________________________________MYLERAN Literaturverzeichnis
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112 Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of busulfan and hydroxyurea in chronic 132 Appelbaum FR, Dahlberg S, Thomas ED, et al. al. Bone myelogenous leukemia: prolongation of survival by marrow transplantation or chemotherapy after remission hydroxyurea. Blood, 1993, 82/2:398-407.
induction for adults with acute nonlymphoblastic leukemia.
113 Hehlmann R, Heimpel H, Kolb HJ et al. The German CML study, comparison of Busulfan vs. Hydroxyurea vs. Interferon 133 Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation alpha and establishment of prognostic score 1.
for the treatment of chronic myelogenous leukemia.
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114 The Italian Cooperative Study Group on Chronic Myeloid 134 Santos GW, Tutschka PJ, Brookmeyer R, et al. Marrow Leukemia: Interferon alpha-2a as compared with conventional transplantation for acute non-lymphocytic leukemia after chemotherapy for the treatment of chronic myeloid leukemia.
treatment with busulfan and cyclophosphamide.
115 Ohnishi K, Ohno R, Tomonaga M, et al. A randomized trial 135 Josvasen N, Boyum A: Hematopoiesis in busulphan treated comparing Interferon-α with Busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase.
136 Santos GW, Tutschka PJ. The effect of busulfan on antibody Blood, 1995, 86, No 3 (Aug 1):906-916.
production and skin allograft survival in the rat.
116 Bergsagel DE und H Messner. The maintenance of busulphan-induced remissions in chronic granulocytic 137 Buckner CD, Dillingham LA, Giddens WE, et al. Toxicologic leukaemia with recombinant interferon α-2b. Br J Cancer, and marrow transplantation studies in rhesus monkeys given dimethylmyleran. Exp Hematol, 1975, 3:275.
117 Aulitzky, WE, Peschel, C, Huber, C. Chronische myeloische 138 Geller RB, Saral R, Piantadosi S, et al. Allogenic bone Leukämie. Aus Schmoll HJ, Höffken K, Possinger K.
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cyclophosphamide in patients with acute non-lymphocytic 118 Galton, DAG. Treatment of the chronic leukaemias.
________________________________________________________________________________MYLERAN 139 Tutschka PJ, Copelan EA, Klein JP. Bone marrow 156 Santos GW, Busulfan and Cyclophosphamide vs.
transplantation for leukemia following a new busulfan and Cyclophosphamide and total body irradiation for marrow cyclophosphamide regimen. Blood, 1987, 70:1382-1388.
transplantation in chronic myelogenous leukemia - a review.
140 Copelan EA, Biggs JC, Thompson JM, et al. Treatment for Leukemia and Lymphoma, 1993, 11, Suppl. 1:201-204.
acute myelocytic leukemia with allogenic bone marrow 157 Brodsky I, Biggs JC, Szer J, et al. Treatment of chronic transplantation following preparation with BuCy2.
myelogenous leukemia with allogenic bone marrow transplantation after preparation with Busulfan and 141 von Bueltzingsloewen A, Belanger R, Perreault C, et al.
Cyclophosphamide (BuCy2): an update.
Acute Graft-versus-Host disease prophylaxis with Seminars in Oncology, 1993, 20, No. 4, Suppl. 4 (Aug):27-31.
methotrexate and cyclosporine after busulfan and 158 Galimberti M, Polchi P, Lucarelli G, et al. Allogenic marrow cyclophosphamide in patients with hematologic malignancies.
transplantation in patients with chronic myeloid leukemia in chronic phase following preparation with busulfan and 142 Copelan EA, Biggs JC, Szer J, et al. Allogenic bone marrow transplantation for acute myelogenous leukemia, acute Bone Marrow Transplantation, 1994, 13:197-201.
lymphocytic leukemia, and multiple myeloma following 159 Clift RA, Buckner CD, Thomas ED, et al. Marrow preparation with busulfan and cyclophosphamide.
transplantation for chronic myeloid leukemia: a randomized Seminars in Oncology, 1993, 20, Nr. 4, Suppl. 4 (Aug.) study comparing Cyclophosphamide and total body 143 Blume KG, Kopecky KJ, Henslee-Downey JP et al. A irradiation with Busulfan and Cyclophosphamide.
prospective randomized comparison of total body irradiation- Blood, 1994, Vol 84, No 6 (Sept 15):2036-2043.
etoposide versus Busulfan-Cyclophosphamide as preparatory 160 Devergie A, Blaise D, Attal M, et al. Allogenic bone marrow regimens for bone marrow transplantation in patients with transplantation for chronic myeloid leukemia in first chronic leukemia who were not in first remission: a Southwest phase: a randomized trial of Busulfan-Cytoxan vs. Cytoxan- total body irradiation as preparative regimen: a report from Blood,, 1993, Vol. 81, No. 8 (Apr 15):2187-2193.
the French Society of Bone Marrow Graft (SFGM).
144 Ringden O, Ruutu T, Remberger M, et al. A randomized trial Blood, 1995, Vol. 85, No. 8, (Apr. 15):2263-2268.
comparing Busulfan with total body irradiation as 161 Wagner JE, Vogelsang GB, Zehnbauer BA, et al. Relapse of conditioning in allogenic marrow transplant recipients with leukemia after bone marrow transplantation: effect of second leukemia: a report from the Nordic bone marrow transplantation group. Blood, 1994, 83/9:2723-2730.
Bone Marrow Transplant., 1992, 9:205-209.
145 Appelbaum FR, Fisher LD, Thomas ED. Chemotherapy v 162 Cullis JO, Schwarer AP, Hughes Therapie, et al. Second marrow transplantation for adults with acute nonlymphocytic transplants for patients with chronic myeloid leukaemia in leukemia. A five-year follow-up. Blood, 1988, 72:179-184.
relapse after original transplant with T-depleted donor 146 McGlave PB, Haake RJ, Bostrom BC, et al. Allogenic bone marrow: feasibility of using busulfan alone for re- marrow transplantation for acute nonlymphocytic leukemia in first remission. Blood, 1988, 72:1512-1517.
147 Blaise D, Maraninchi D, Archimbaud E, et al. al. Allogenic 163 Schmitz N. Allogene Knochenmarktransplantation bei bone marrow transplantation for acute myeloid leukemia in chronischer myeloischer Leukämie. Ergebnisse aus HLA- first remission: A randomized trial of a busulfan-cytoxan identischer Transplantation in der Bundesrepublik versus cytoxan-total body irradiation-etoposide vs. busulfan- Deutschland. Dtsch. med. Wschr., 1990, 115:923-929.
cyclophosphamide as preparatory regimens for bone marrow 164 Yeager AM, Kaizer H, Santos GW, et al. Autologous bone transplantation in patients with leukemia who were not in first marrow transplantation in patients with acute nonlymphocytic remission: a Southwest Oncology Group Study.
leukemia, using ex vivo marrow treatment with 4- Blood, 1993, 81, No. 8 (Apr 15):2187-2193.
148 Linker CA, Damon LE, Ries CA et al. Busulfan plus etoposide as a preparative regimen for autologous bone 165 Dusenbery KE, Daniels KA, McClure JS, et al. Randomized marrow transplantation for acute myelogenous leukemia: an comparison of cyclophosphamide-total body irradiation vs update. Seminars in Oncology, 1993, Vol. 20, No. 4, Suppl. 4 Busulfan-Cyclophosphamide conditioning in autologous bone marrow transplantation for acute myeloid leukemia. Int. J.
149 Tutschka PJ, Copelan EA and N Kapoor. Replacing total Radiation Oncology Biol. Phys., 1995, Vo. 31, No. 1:119- body irradiation with Busulfan as conditioning of patients with leukemia for allogenic marrow transplantation.
166 Chao NJ, Stein AS, Long GD, et al. Busulfan/Etoposide - Transplantation Proceedings, 1989, Vol 21, No. 1:2952-2954.
Initial experience with a new preparatory regimen for 150 Beelen DW, Quabeck K, Mahmoud HK, et al.
autologous bone marrow transplantation in patients with acute Remissionserhaltende Therapie der akuten myeloischen nonlymphoblastic leukemia. Blood, 1993, 81/2:319-323.
167 Avalos BR, Klein JL, Kapoor N, et al. Preparation for marrow transplantation in Hodgkin´s and non-Hodgkin´s lymphoma Dtsch. med. Wschr., 1991, 116:401-410.
using Bu/Cy. Bone Marrow Transplant., 1993, 12/2:133-138.
151 Lynch MHE, Petersen FB, Appelbaum FR, et al. Phase II 168 Spitzler TR, Cottler-Fox M, Torrisi J, et al. Escalating doses study of busulfan, cyclophosphamide and fractionated total of etoposide with cyclophosphamide and fractionated total body irradiation as a preparatory regimen for allogenic bone body irradiation or busulfan as conditioning for bone marrow marrow transplantation in patients with advanced myeloid transplantation. Bone Marrow Transplant, 1989, 4:559-565.
malignancies. Bone Marrow Transplantation, 1995, 15:59-64.
169 Vaughan WP, Dennison JD, Reed EC, et al. Improved results 152 Copelan EA, Biggs JC, Avalos BR et al. Radiation-free of allogenic bone marrow transplantation for advanced preparation for allogenic bone marrow transplantation in hematologic malignancy using busulfan, cyclophosphamide adults with acute lymphoblastic leukemia.
and etoposide as cytoreductive and immunosuppressive therapy. Bone Marrow Transplant., 1991, 8:489-495.
153 Lenarsky C, Weinberg K, Kohn DB, et al. Bone marrow 170 Geller RB, Myers S, Devine S, et al. Phase I study of transplantation for children with acute lymphoblastic busulfan, cyclophosphamide and timed sequential escalating leukemia with busulfan and cyclophosphamide.
doses of cytarabine followed by bone marrow transplantation.
Bone Marrow Transplant, 1992, 9:41-47.
154 Zander, A. Praxis der allogenen Knochenmarktransplantation 171 Buckner CD, Fefer A, Bensinger WI, et al. Marrow transplantation for malignant plasma cell disorders: Summary Krankenhausarzt (Forum), 1992, 65, 9:445-448 of the Seattle experience. Eur J Haematol, 1989, 43:186-190.
155 Santos GW. Review article: marrow transplantation in acute 172 Bensinger WI, Buckner CD, Clift RA, et al. Phase I Study of nonlymphocytic leukemia. Blood, 1989, 74:901-908.
Busulfan and Cyclophosphamide in preparation for allogenicmarrow transplant for patients with multiple myeloma.
J Clin Oncol, 1992, 10/9:1492-1497.
________________________________________________________________________________MYLERAN 173 Mansi J, de Costa F, Viner C, et al. High dose Busulfan in 191 Przepiorka D, Nath R, Ippoliti C, et al. A phase I-II Study of patients with myeloma. J Clin Oncol, 1992, 10/10:1569-1573.
high-dose thiotepa, busulfan and cyclophosphamide as a 174 Dimopoulos MA, Alexanian R, Przepiorka D, et al. Thiotepa, preparative regimen for autologous transplantation for Busulfan, and Cyclophosphamide: A new preparative regimen for autologous marrow or blood stem cell transplantation in Leukemia and Lymphoma, 1995, Vol. 17:427-433.
high-risk multiple myeloma. Blood, 1993, 82/8:2324-2328.
192 Przepiorka D, Ippoliti C, Giralt S, et al. A phase I-II study of 175 Schiller G, Nimer S, Vescio R, et al. Phase I-II study of high-dose thiotepa, busulfan and cyclophosphamide as a busulfan and cyclophosphamide conditioning for preparative regimen for allogenic marrow transplantation.
transplantation in advanced multiple myeloma.
Bone Marrow Transplantation, 1994, 14:449-453.
Bone Marrow Transplantation, 1994, 14:131-136.
193 Weaver CH, Bensinger WI, Appelbaum FR, et al. Phase I 176 Woods WG, Kobrinsky N, Buckley J, et al. Intensively times study of high-dose busulfan, melphalan and thiotepa with induction therapy followed by autologous or allogenic bone autologous stem cell support in patients with refractory marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: A Childrens Cancer Bone Marrow Transplantation, 1994, 14:813-819.
Group pilot study. J Clin Oncol, 1993, 11:1448-1457.
194 Becher R und G Prescher. Biclonal Analysis of Busulfan- 177 Lenarsky C, Weinberg K, Petersen J, et al. Autologous bone induced sister chromatid exchange in blast crisis of Philadelphia chromosome-positive chronic myeloid leukemia.
hydroperoxycyclophosphamide purged marrows for children Cancer Genet Cytogenet, 1991, 52:71-78.
with acute non-lymphoblastic leukemia in second remission.
195 Ehling UH, Neuhäuser-Klaus A. Induction of specific-locus Bone Marrow Transplant, 1990, 6:425-429.
and dominant lethal mutations in male mice by busulfan.
178 Nespoli L, Locatelli F, Zecca M. Busulfan as part of Mutation Research, 1991, 249:285-292.
conditioning regimen for bone marrow transplantation in 196 Bucci LR and ML Meistrich. Effects of busulfan on murine children. Bone Marrow Transplantation, 8 Suppl. 1:30-2, spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations. Mutat Res, 1987, 176:259- 179 Sanders JE, Pritchard S, Mahoney P, et al. Growth and development following marrow transplantation for leukemia.
197 Kenis, Y et al. Action du Myleran dans 22 cas des leucemie myeloide chronique. (Action of Myleran in 22 cases of 180 Wingard JR, Plotnick LP, Freemer CS, et al. Growth in chronic myeloid leukaemia) Revue Francaise Etudes Clinique children after bone marrow transplantation: Busulfan plus Cyclophosphamide vs. Cyclophosphamide plus total body 198 Wilkinson JF & RL Turner. Chemotherapy of chronic irradiation. Blood, 1992, 79/4:1068-1073.
myeloid leukaemia, with special reference to Myleran.
181 Giorgiani G, Bozzola M, Locatelli F, et al. Role of Busulfan Progress in Haematology, 1959, 2:225-238.
and total body irradiation on growth of prepubertal children 199 Burns WA et al. Toxic manifestations of busulfan therapy.
receiving bone marrow transplantation and results of Medical Annals of the District of Columbia, 1971, 40:567- treatment with recombinant human growth hormone.
Blood, 1995, Vol. 86, No. 2 (July 15):825-831.
200 Shalev O, Rahav G and A Milwidsky. Reversible busulfan- 182 Shaw PJ, Bergin ME, Burgess MA, et al. Childhood acute myeloid leukemia: outcome in a single center using Eur J Obstet Gynecol Reprod Biol, 1987, 26:239-242.
201 Lopez-Ibor B & AD Schwartz. Gonadal failure following Busulfan/Cyclophosphamide for bone marrow busulfan therapy in an adolescent girl.
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J of Clin Oncol, 1994, Vol. 12, No. 10 (Oct.):2138-2145.
202 Vergauwen P, Ferster A, Valsamis J, et al. Primary ovarian 183 Kalifa C, Hartmann O, Demeocq F, et al. High-dose busulfan failure after prepubertal marrow transplant in a girl.
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childhood malignant brain tumors: a phase II study.
203 Wingard JR, Miller DF, Santos GW. Testicular function after Bone Marrow Transplant, 1992, 9/4:227-233.
184 Loiseau HA, Hartmann O, Valteau D, et al. High-dose J Cell Biochem, 1992, 16 A:216 (abstr. D618).
chemotherapy containing busulfan followed by bone marrow 204 Diamond I, Anderson MM, McCreadie, SR. Transplacental transplantation in 24 children with refractory or relapsed non- transmission of Busulfan (Myleran) in a mother with leukemia. Pediatrics, January 1960:85-90.
Bone Marrow Transplant, 1991, 8/6:465-472.
205 Bhisey, AN, SH Advani and AG Khare. Cytogenic anomalies 185 Graham ML, Yeager AM, Leventhal BG, et al. Treatment of in a child born to a mother receiving busulfan for chronic recurrent and refractory pediatric solid tumors with high-dose myeloid leukemia. Indian J of Cancer, 1982, 19:272-276.
busulfan and cyclophosphamide followed by autologous bone 206 Doll DC, Ringenberg S and JW Yarbro. Antineoplastic agents marrow rescue. J Clin Oncol, 1992, 10/12:1857-1864.
and pregnancy. Semin Oncol, 1989, 16/5:337-346.
186 Schultz KK, Ratanatharathorn V, Abella E, et al. Graft failure 207 Moloney WC. Management of leukemia in pregnancy. Annals in children receiving HLA-mismatched marrow transplants of the New York Academy of Sciences, 1964, 114:857-867.
208 Nicholson HO. Cytotoxic drugs in pregnancy. Journal of Bone Marrow Transplantation, 1994, 13:817-822.
Obstetrics and Gynaecology of the British Commonwealth.
187 Klumpp TR, Mangan KF, Glenn LD et al. Phase II pilot study of high-dose busulfan and CY followed by autologous BM or 209 Shalev O et al. Reversible busulfan-induced ovarian failure.
peripheral blood stem cell transplantation in patients with Eur J of Obstetrics, Gynecology and Reproductive Biology, advanced chemosensitive breast cancer.
Bone Marrow Transplant, 1993, 11/4:337-339.
210 Norhaya MR, Cheong SK, Hamidah NH, et al. Pregnancy in a 188 Galimberti M, Polchi P, Lucarelli G, et al. Bone marrow patient receiving busulfan for chronic myeloid leukemia.
transplantation in thalassemia after Busulphan and Singapore Medical Journal, 1994, 35 (1):102-103.
Cyclophosphamide. Report on 88 Cases.
211 Schmahl, D and H Osswald. Experimental studies on the Annals of the NY Academy of Sciences, 1987, 511:464-467.
carcinogenic effects of anticancer chemotherapeutics and 189 Andreani M, Centis F, Lucarelli G, et al. Immunologic recovery in thalassemic marrow graft recipients following Arzneim. Forsch., 1970, 20:1461-1467.
high-dose Busulfan and Cyclophosphamide.
212 Juch E, Lauterbach A. Dysplastische Veränderungen am Transplantation, 1988, Vol. 46, No. 3:394-398.
Epithel der Cervix uteri durch Busulfan (Myleran).
190 Przepiorka D, Dimopoulos M, Smith T, et al. Thiotepa, Geburtsh. und Frauenheilk., 42 (1982):43-44.
busulfan, and cyclophosphamide as a preparative regimen for 213 Aksoy M, Erdem S, Bakioglu I, et al. Endometrial cancer due marrow transplantation: risk factors for early regimen-related toxicity. Ann Hematol, 1994, 68:183-188.
J cancer Res Clin Oncol, 1984, 108:362-363.
________________________________________________________________________________MYLERAN 214 Nelson BM & Andrews GA. Breast cancer and cytologic 241 Schallier D et al. Additive pulmonary toxicity with melphalan dysplasia in many organs after busulfan (Myleran).
and busulphan therapy. Chest, 1983, 84:492-493.
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242 Massin F, Fur A, Reybet-Degat O, et al. La pneumopathie du 215 Feingold ML & Koss LG. The effects of long term busulfan. Rev Mal Resp, 1987, 4:3-10.
243 Koss LG, Melamed MR, Mayer K. The effect of Busulfan on Archives of Internal Medicine, 1969, 124:66-71.
human epithelia. Am J Clin Pathol., 1965, 44:385-397.
216 Landaw SA. Acute leukemia in polycythemia vera.
244 Beschorner WE et al. Pathology of the liver with bone Seminars in Hematology, 1986, 23:156-165.
marrow transplantation. Am J of Pathology, 1980, 99:369- 217 Dittmar, K. Acute myeloblastic leukemia with polycythemia vera, treated with busulfan and phlebotomy.
245 Key NS et al. Oesophageal varices associated with busulphan- NY State J Med., 1979, 75 (5), 758-761.
thioguanine combination therapy for chronic myeloid 218 Stott, H, W Fox, DJ Girling, et al. Acute leukemia after leukaemia. Lancet ii, 1987:1050-1052.
246 Underwood JCE et al. Jaundice after treatment of leukaemia with busulphan. Br Med Journal, 1971, 1:556-557.
219 IARC. Evaluation of the Carcinogenic Risk of Chemicals to 247 Hast R. Increase in serum alkaline phosphatase (S-ALP) in Human. Monograph Suppl. 4 IARC. Lyon, 1982:18.
chronic myelocytic leukemia: sign of drug-induced 220 Elson LA. Hematological effects of the alkylating agents.
cholestasis? Acta Medica Scandinavica, 1978, 203:93-94.
248 Morris LE, Guthrie TH. Busulfan-induced hepatitis.
221 McManus Polymerase & L Weiss. Busulphan-induced Am J Gastroenterology, 1988, Vol. 83, No. 6:682-683.
chronic bone marrow failure: changes in cortical bone, 249 Bronner AK & AF Hood. Cutaneous complications of marrow stromal cells and adherent cell colonies.
J Am Academy of Derm, 1983, 9:645-663.
222 Mollneux G, Testa NG, Massa G, et al. An analysis of 250 Harrold BUSULPHAN. Syndrome resembling Addison´s haematopoietic and microenvironmental populations of disease following prolonged treatment with busulphan.
mouse bone marrow after treatment with busulphan.
Biomedical Pharmacotherapy, 1986, 40, 215-220.
251 Leyden MJ & A Manoharan. „Allopurinol-type“ rash due to 223 Finney R, McDonald, Baikie AG, et al. al. Chronic granulocytic leukemia with Ph negative cells in bone marrow 252 Haut A et al. The use of Myleran in the treatment of chronic and a 10 year transmission after busulfan hypoplasia.
Archives of Internal Med, 1955, 96:451-462.
224 Haut A, Abbot WS, Wintrobe MM, et al. Busulphan in the 253 Sidy Y, Douer D, Pinkhas J. Sicca Syndrome in a patient with treatment of chronic myelocytic leukemia. The effect of long- toxic reaction to busulfan. JAMA, 1977, 238:1951.
term intermittent treatment. Blood, 1969, 17, 1.
254 Cohen RE et al. Prevalence and correlates of post-treatment 225 Perol C, Najeen Y, Tanzer J, et al. Les aplasies du Busulfan and anticipatory nausea and vomiting in cancer au cours des lecemies myeloides chronique.
chemotherapy. J Psychosomatic Research, 1986:30, 643-654.
Nouvell Revue Francaise d´Hématologie, 1967, 7, 884-889.
255 Haut A, et al. Busulfan in the treatment of chronic myelocytic 226 Thiele J, Kvasnicka HM, Niederle N, et al. The impact of leukemia. Archives of Internal Med, 1955, 96:451-462.
interferon versus busulfan therapy on the reticulin stain- 256 Podos SM & GP Canellos. Lens changes in chronic measured fibrosis in CML - a comparative morphometric granulocytic leukemia: possible relationship to chemotherapy.
study on sequential trephine biopsies.
Am J Ophthalmology, 1969, 68:500-504.
257 Dahlgren S et al. Clinical and morphological side effects of 227 Shepherd PCA, Richard S and NC Allan. Severe cytopenias associated with the sequential use of busulfan and interferon- Acta medica Scandinavica, 1972, 192:129-135.
258 Ravindranathan MP et al. Cataract after busulphan treatment.
228 Fernandez LA and E Zayed. Busulfan induced sideroblastic 259 Fraunfelder FT, Meyer SM. Ocular toxicity of antineoplastic anemia. Am J Hematol, 1988, 28/3:199-200.
229 Oliner H, Schwartz R, Rubio F, et al. Interstitial pulmonary Am Academy of Ophthalmology, 1983, Vol. 90, No 1:1-3 fibrosis following busulfan therapy.
260 Galton DAG. Chemotherapy of chronic myelocytic leukemia.
Seminars in Haematology, 1969, 6:323-343.
230 About I, Lauque D, Levenes H, et al. Opacités alvéolaires et 261 Millard RJ. Busulfan-induced hemorrhagic cystitis.
al. pneumopathie au busulfan. Rev Mal Resp, 1992, 9:39-41.
231 Pearl M. Busulfan lung. Am J of Diseases of Children, 1977, 262 Djaldetti M et al. Myasthenia gravis in a patient with chronic myeloid leukemia treated by busulfan.
232 Muggia FM et al. Pulmonary toxicity of antitumor agents.
Cancer Treatment Reviews, 1983, 10:221-243.
263 Méresse V, Hartmann O, Vassal G, et al. Risk factors for 233 Batist G & JL Andrews. Pulmonary toxicity of antineoplastic hepatic veno-occlusive disease after high-dose busulfan- drugs. J Am Med Association, 1981, 246:1449-1453.
containing regimens followed by autologous bone marrow 234 Brynes RD et al. Diagnosis of busulfan lung by transcatheter transplantation. Bone Marrow Transplant., 1992, 10:135-141.
264 Mac Donal GB, Hinds MS, Fischer LD et al. Veno-occlusive 235 Green GI et al. Busulfan lung complicated by Pneumocystis disease of the liver and multiorgan failure after bone marrow carinii and cytomegalovirus infection.
transplantation: a cohort study of 355 patients.
Med Annals of the District of Columbia, 1974, 43:124-128.
236 Massin F et al. La pneumopathie du busulfan.
265 Vassal G, Doeroussent A, Hartmann O et al. Dose-dependent Revue Francaise des Maladies Respiratoires, 1987, 4:3-10.
neurotoxicity of high-dose busulfan in children: a clinical and 237 Kuplic JB et al. Pulmonary ossification associated with long pharmacological study. Cancer Res, 1990, 50:6203-6207.
term busulfan therapy in chronic myeloid leukemia. Case 266 Meloni G, Raucci U, Pinto RM, et al. Pretransplant report. Am Review of Respiratory Diseases, 1972, 106:759- conditioning with busulfan and cyclophosphamide in acute leukemia patients: neurological and electroencephalographic 238 Ginsberg SJ & RL Comis. The pulmonary toxicity of prospective study. Ann Oncol, 1992, 3:145-148.
antineoplastic agents. Seminars in Oncology, 1982, 9:34-51.
267 Murphy CP, Harden EA and Thompson JM: Generalized 239 Soble AR & H Perry. Fatal radiation pneumonia following seizures to high-dose busulfan therapy.
Am J Roentgenology, 1977, 128:15-18.
268 Teshima H, Masaoka T, Inoue T, et al. Interstitial 240 Hankins DG et al. Pulmonary toxicity after a six week course pneumonitis in allogenic bone marrow transplantation: a of busulfan therapy and after subsequent therapy with uracil report from the Japanese BMT study group.
Bone Marrow Transplant, 1986, 1:179-183.
________________________________________________________________________________MYLERAN 269 Wingard JR, Sostrin MB, Vriesendorp HM et al., Interstitial 288 Brodsky R, Topolsky D, Crilley P et al. Frequency of veno- pneumonitis following autologous bone marrow occlusive disease of the liver in bone marrow transplantation transplantation. Transplantation, 1988, 46:61-65.
with a modified Busulfan/Cyclophosphamide preparative 270 Nevill TJ, Barnett MJ, Klingemann H-G, et al. Regimen- regimen. Am J Clin Oncol, 1990, 13/3:221-225.
related toxicity of a busulfan-related toxicity of a busulfan- 289 Essell JH, Thompson JM, Harman G et al. Marked increase in cyclophosphamide conditioning regimen in 70 patients veno-occlusive disease of the liver associated with undergoing allogenic bone marrow transplantation. J Clin methotrexate use for Graft-versus-Host Disease prophylaxis in patients receiving Busulfan/Cyclophosphamide.
271 MacDonald GB, Sharma P, Matthews DE, et al. The clinical course of 53 patients with veno-occlusive disease of the liver 290 Bishop JB & JS Wassom. Toxicological review of busulfan (Myleran). Mutation Research, 1986, 168:15-45.
291 Hymes SR, Simonton SC, Farmer ER et al. Cutaneous 272 Bearman SI, Appelbaum FR, Buckner CD et al. Regimen- busulfan effect in patients receiving bone-marrow related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol, 1988, 6:1562-1568.
J Cutaneous Pathology, 1985, 12:125-129.
273 Shaw PJ, Hugh-Jones K, Hobbs JR, et al. Busulphan and 292 Terpstra W, de Maat CEM. Pericardial fibrosis following cyclophosphamide cause little early toxicity during displacement bone marrow transplantation in fifty children.
Netherlands Journal of Medicine, 1989, 35:249-252.
Bone Marrow Transplant, 1986, 1:193-200.
293 Clark JG, Schwartz DA, Flournoy N, et al. Risk factors for 274 Filipovich AM, Shapiro RS, Ramsay NKC, et al. Unrelated airflow obstruction in recipients of bone marrow donor bone marrow transplantation for correction of lethal transplantation. Ann Intern Med, 1987, 107:648.
congenital immunodeficiencies. Blood, 1992, 80:270-276.
294 Prince DS, Wingard JR, Saral R, et al. Longitudinal changes 275 Ratanatharathon V, Karanes C, Lum LG, et al. Allogenic in pulmonary function following bone marrow bone marrow transplantation in high risk myeloid disorders transplantation. Chest, 1989, 96:301.
using busulfan, cytosine arabinoside and cyclophosphamide 295 Van der Jagt RHC, Appelbaum FR, Petersen FB, et al.
(BAC). Bone Marrow Transplant, 1992, 9:49-55.
Busulfan and cyclophosphamide as a preparative regimen for 276 Crilley P, Topolsky D, Styler MJ et al. Extramedullary bone marrow transplantation in patients with prior chest toxicity of a conditioning regimen containing busulphan, radiotherapy. Bone Marrow Transplant, 1991, 8:211-215.
cyclophosphamide and etoposide in 84 patients undergoing 296 Crilley I, Topolski D, Bulova S, Bone marrow transplantation autologous and allogenic bone marrow transplantation.
following busulphan and cyclophosphamide for acute Bone Marrow Transplantation, 1995, 15: 361-365.
277 Bandini G, Belardinelli A, Rosti G et al. Toxicity of high- Bone Marrow Transplant, 1990, 5:187-191.
dose busulphan and cyclophosphamide as conditioning 297 Martell RW, Sher C, Jacobs P et al. High-dose busulfan and therapy for allogenic bone marrow transplantation in adults myoclonic epilepsy. Ann Intern Med, 1987, 106:1973.
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