BACKGROUND Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small‐volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine‐131 (131I)–labeled humanized anti–carcinoembryonic antigen (anti‐CEA) antibody (MAb) hMN‐14 in small‐volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this 131I‐labeled humanized anti‐CEA antibody in colorectal cancer patients with small‐volume disease or in an adjuvant setting. METHODS Thirty colorectal cancer patients, with small‐volume metastatic disease (n = 21; all lesions ≤ 3.0 cm, and chemorefractory to 5‐fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4–6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of 131I‐hMN‐14 immunoglobulin G at a 60 mCi/m2 dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow‐up was obtained at 3‐month intervals for as long as 36 months. RESULTS At a mean blood‐based red marrow dose of 1.8 ± 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60‐mCi/m2 dose level at 8–16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection. CONCLUSIONS These data suggest that RIT is a safe and effective form of therapy for small‐volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko‐ and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated. Cancer 2002;94:1373–81. © 2002 American Cancer Society. DOI 10.1002/cncr.10308
The (E}-I-hetaryl-2-propen-I-ones 3 and 4 are prepared by condensation of 2-acetylthiophenes (1a,1c:.ld)or 2-acetylfuran (Ib) with aldehydes. The Michael addUC\S 5/6 areobtained from 3/4 by reactionwith malononitrile/1..DA in TIIF at -78OC. or in OMSOwith NaH at room temp.Reactionof 3/4 with malononitrile and methylate in methanol yielded the substituted nicotinonitriles 7/8. From terephthalaldehyde. the diketones 9 are prepared,whichyield with malononitrile the phenylene-bis[(thienyVfuryl)nicotinonitrilel derivatives 10 undersimiliarconditions. StruetUrat and spectraldata are discussed.2-Acetylated thiophenes and furans 1 are versatile starting materials for many classes of heterocyclesi', We are especially interested in the construction of highly substituted pyridines and related heterocycles starting from 1,4-pentadien-3-ones and other substituted C1,~unsaturated ketones by Michael and similiar reactions 3 ). Here, we report about the reactions of 1 with aromaticaldehydes2 and malononitrile.Referring to a prescription given by Murphy and Watta· nasin 4 ) la was reacted with the aldehydes 2a-i in absol. methanol in the presence of NaOH. The (l,l3-unsaturated ketones 3a-i (Scheme 1) were obtained in yields between 80 and 90%5). 3y was prepared from Ic, and 3z from Id, By a similiar procedure, from Ib the unsaturated ketones 4a-i were obtained.According to spectroscopic data, all compounds 3/4 exist in the E-configuration. Their IR-spectra show a strong carbonyl absorption around 1640 em", and the C=C absorption appears between 1590 and 1600 em", The out-of-plane vibration bond at 980 cm' is a characteristic of trans alkenes. form", a.13-Unsaturated ketones with E-configuration usually prefer the s-trans conformatlonv", As the propenones 3 and 4 contain the l,4-pentadien-3-one system -one double bond of the system is included in the heteroaromatic ring -it might be of interest to know, whether these compounds exist in different conformers as shown in Scheme 2. The system is flexible, and, therefore. an equilibrium of at least four conformations should be possible in solution, and it was of special interest to see if 3 and 4 even prefer one conformation. Perhaps, the i.r, spectra suggest a preferred sods conformation as indicated by the ratio Ico/Ic-e, and by the difference of 50-60 em" between both bands. Using the ASIS effect lO ) (deuterochloroforrn/deuterobenzene), we demonstrated that the s-transls-cis conformation A is the preferred one in solution. The differences in the shifts of the l3-protons, Sc6D6 -SCDC13' vary between +0.05 and +0.3 ppm ll ) (Table 1).
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Cyclopropane derivatives Q 0021Reactions of Heteroaryl Substituted Propenones. -Thienyl-and furylpropenones (I) react with sulfur ylide (II) yielding heteroaryl substituted cyclopropyl ketones (III) which are transformed into dihydrobenzofuranone and -thiophenone (IV), or γ-hydroxy ketones (V) and (VI) by reaction of cyclopropyl ketones with Lewis acids. Reaction of (I) with activated methylene compounds (VII) and (XI) affords the corresponding addition products which can be cyclized to heteroaryl substituted dihydropyranes, e.g.IX), cyclohexanols, e.g. (XII) and piperidones, e.g. (XIV). Compounds (XII) and (XIV) are examples of unusual cyclization products. In addition, cycloadditions with thiophene derivatives enable the synthesis of substituted benzothiophene derivatives, but with poor yields. -(GREINER-BECHERT, L.; SPRANG, T.; OTTO*, H.-H.; Monatsh. Chem. 136 (2005) 4, 635-653; Inst. Pharm./Med. Chem.,
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