The conditioning regimen prior to stem cell transplantation in 36 patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) was intensified by treating patients with a rhenium 188-labeled anti-CD66 monoclonal antibody. Dosimetry was performed prior to therapy, and a favorable dosimetry was observed in all cases. Radioimmunotherapy with the labeled antibody provided a mean of 15.3 Gy of additional radiation to the marrow; the kidney was the normal organ receiving the highest dose of supplemental radiation (mean 7.4 Gy). Radioimmunotherapy was followed by standard full-dose conditioning with total body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide with or without thiotepa. Patients subsequently received a T-cell-depleted allogeneic graft from a HLA-identical family donor (n ‫؍‬ 15) or an alternative donor (n ‫؍‬ 17). In 4 patients without an allogeneic donor, an unmanipulated autologous graft was used. Infusion-related toxicity due to the labeled antibody was minimal, and no increase in treatment-related mortality due to the radioimmunoconjugate was observed. Day ؉30 and day ؉100 mortalities were 3% and 6%, respectively, and after a median follow-up of 18 months treatment-related mortality was 22%. Late renal toxicity was observed in 17% of patients. The relapse rate of 15 patients undergoing transplantation in first CR (complete remission) or second CR was 20%; 21 patients not in remission at the time of transplantation had a 30% relapse rate. (Blood. 2001;98:565-572)

Here we report the expression of major pyrimidine metabolising enzymes in pancreatic cancer cell lines, chronic pancreatitis tissue and human pancreatic cancer and the in vitro uptake of 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]FLT). The expression of pyrimidine metabolising enzymes was evaluated with real-time PCR, Western blot and immunostaining. Thymidine kinase 1 (TK-1) activity was measured with a fluorocytometric assay. The cellular uptake and intracellular metabolism of [(18)F]FLT were evaluated in pancreatic lobules and in transformed cancer cell lines. TK-1 and thymidine synthetase mRNA were increased in six pancreatic cancer cell lines, while mRNA levels of thymidine kinase 2 and deoxycytidine kinase were down-regulated. High TK-1 activity was confirmed in all cell lines. Furthermore, TK-1 was overexpressed in human pancreatic cancer as compared with normal pancreatic tissue and samples from patients with chronic pancreatitis. The cellular uptake of [(18)F]FLT was 18.4%+/-3.6% and 5.2%+/-1.4% of the applied radioactivity after 240 min in SW-979 and BxPc-3 cells, respectively, while uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG) was only 0.6%+/-0.04% (SW-979) and 0.3%+/-0.13% (BxPc-3) after 240 min of incubation. In contrast, cellular uptake of [(18)F]FLT in isolated pancreatic lobules and growth-arrested HT1080 cells was lower as compared with the uptake of [(18)F]FDG and with the malignant pancreatic cancer cell lines. HPLC analysis of the perchloric acid-soluble cell fraction demonstrated the phosphorylation of [(18)F]FLT to the respective monophosphate in both cell lines. Furthermore, 0.8%+/-0.12% (BxPc-3) and 1.3%+/-0.38% (SW-979) of the applied radioactivity was detected in the perchloric acid-insoluble cell fraction, indicating the incorporation of [(18)F]FLT into the DNA. Our results demonstrate the cellular uptake, intracellular trapping and incorporation into the DNA of [(18)F]FLT in pancreatic cancer cells in vitro. TK-1, as the rate-limiting enzyme of [(18)F]FLT metabolism, is overexpressed in pancreatic cancer cell lines and in human pancreatic cancer. Thus, we propose [(18)F]FLT as a promising tracer for positron emission tomography that might overcome current limitations in the diagnosis of pancreatic cancer.

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (188Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2+/-2.1 (range 6.9-15.8) GBq 188Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4+/-5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.

t,l-Dicyan-2-aryl-l ,8a-dihydroazulene 6(a -g) werden ausgehend von 8-Methoxyheptafulven und Benzylidenmalonodinitrilen iiber Tetrahydroazulene 5 dargestellt. Die Dihydroazulene 6 lagern durch sichtbares Licht in 8-(2,2-Dicyan-l-arylvinyl)heptafulvene 7 um. Die Riickreaktion 7+6 erfolgt thermisch. Die chemische Stabilitat und damit die Zahl der reversiblen Cyclen des oszillierenden Gleichgewichts 6+7 hangt von den Substituenten der Arylreste ab. Die p-Methoxyverbindungen 6f, I f haben im Vergleich zu den p-Nitroverbindungen hohere photochemische Stabilitat. Die Struktureigenschaften von 6 und 7 wurden durch Kristallstrukturanalysen von 6c und 7f gesichert. Spektroskopische Daten von 6, 7 sind angegeben. Erste Ergebnisse uber die Umwandlung 6 e 7 im Festzustand liegen vor.Light-Induced and Reversible Transformations: Syntheses and Properties of Photochromic 1,l-Dicyano-1,Iadihydroazulenes and Thermochromic &(2,ZDicyanovinyl)heptafulvenes ') 1,l -Dicyano-2-aryl-l,8a-dihydroazulenes 6(a -8) are prepared in a two-step synthesis starting from 8-methoxyheptafulvene and benzylidenemalononitriles via the tetrahydroazulenes 5. The compounds 6(a -h) rearrange to 8-(2,2-dicyano-I-arylvinyl)heptafulvenes 7(a -h) by irradiation with visible light. The back reaction of 7 to 6 occurs under thermal conditions. Donor-substituted compounds indicate higher long term stability of the equilibrium 6+7 (6f+7f > 44 h). Spectroscopic data of 6 and 7 are given. The molecular structures of the p-bromophenyl derivative 6c and of the p-methoxyphenyl derivative 7f are revealed through crystallography. Some results for the rearrangements 6 s 7 in the solid state are given. lJ3a-Dihydroazulen (1) erweist sich als chemisch sensibler molekularer Baustein. Das Dimethylderivat 2, ein Trinorsesquiterpen, wurde in optisch aktiver Form zusammen mit dem Indenaldehyd 3 und 1,4-Dimethylazulen (4) aus Kulturen von Lebermoos (Calypogeia granulata Inoue) isoliert 'sq. Die Bildung von 4 weist auf die leichte Dehydrierung von 2 hin. Andere Eigenschaften hat die Dicyanverbindung 6. Diese ist photochrom, sichtbares Licht bewirkt eine Umlagerung zu einer tiefroten Substanz, fur die die Struktur des Heptafulvens 7 vorgeschlagen wurde l).Diese photochemische Umwandlung weist auf die Labilitat der C-1 -C-8a-Bin-0 VCH Verlagsgesellschaft mbH, D

Three kava pyrones, the natural compounds (+) methysticine and (+)-kavain, and the synthetic racemate (±)kavain, were tested concerning their action on in vitro uptake of monoamines in synaptosomes prepared from the cerebral cortex and hippocampus of rats. (±)-Kavain and (+)-kavain were found to potently inhibit the uptake of [3H]-noradrenaline. Uptake of [3H]-noradrenaline was inhibited in the following order of potency: (±)-kavain = (+)-kavain > (+)-methysticine, whereas none of the kava pyrones efficiently blocked the uptake of [3H1serotonin. The results indicate a pyrone-specific non-stereoselective inhibition of the [3H]-noradrenaline uptake which might be responsible for or, at least, contribute to the psychotropic properties of kava pyrones. At low dosages, kava pyrones are mainly characterized by their psychotropic action which resembles that of benzodiazepines