Six azocalix[4]arenes were synthesized for the first time by diazo-coupling reactions with calix[4]arene. The products showed unusual spectral properties including an azophenol–quinine–hydrazone tautomerism. Owing to the chromophoric nature, the four pKa’s for water-soluble p-(4-trimethylammoniopheylazo)calix[4]arene could be determined to be 0.5, 2.0, 10.0, and ca. 13. The marked pKa split was explained by the strong hydrogen-bonding interactions characteristic of calix[4]arene.

Diazo coupling between calix[4]arene and five substituted benzenediazonium ions in tetrahydrofuran at 5 "C in the presence of pyridine afforded the tetrasubstituted calixC43arenes as main products and small amounts of mono-, di-and tri-substituted calix [4]arenes even in the presence of unchanged calix[4]arene: the unusual autoaccelerative substitution reaction is attributed t o the specific hydrogenbonding effect among the calix[4]arene OH groups. The products were applied as new 'chromophoric calix[4]arenes,' which selectively recognised Li'.

No abstract

A series of 4 beta-alkyl (7-10), 4 beta-aminoalkyl (12a-y), and 4 beta-amidoalkyl derivatives (14a-g) of 4'-O-demethyl-4-desoxypodophyllotoxin have been synthesized, and their cytotoxicity, inhibition of DNA topoisomerase II (Topo II), and tubulin polymerization were evaluated. All derivatives of 12a-y and 14a-g did not inhibit tubulin polymerization. Many compounds exhibited cytotoxicity and inhibition of Topo II. In particular, 12o, 12s, 12t, and 12u strongly inhibited Topo II (IC50 (microM) 32.5, 60.9, 58.8, and 33.6, respectively) and were strong cytotoxicity against P388 cells (IC50 (M) 1.0, 4.1, 3.3, and 3.0 x 10(-9), respectively), compared with VP-16 (IC50 (microM) 59.2, IC50 (M) 1 x 10(-8), respectively). These compounds were nearly equal to or superior to VP-16 in antitumor activity in vivo (L1210, P388, and Lewis lung) and were more cytotoxic against various human cell lines in vitro than VP-16.

No abstract

TAT-59 suppressed the growth of DMBA-induced mammary tumors in rats earlier and more strongly than tamoxifen (TAM). After oral administration of the drugs, DP-TAT-59, one of the main metabolites of TAT-59, was found in 10- to 15-fold higher concentrations in both the tumor and blood compared to 4-OH-TAM, an active metabolite of TAM. In a 3-day antiuterotrophic test, every detected metabolite of TAT-59 showed stronger antiestrogenic activity than did TAM. In a competition assay, the affinity of the metabolites for estrogen receptors ranged from that of estradiol to that of TAM. These results suggest that the superior antiestrogenic activity of TAT-59 compared to TAM was either due to its higher penetration into tumor tissue or to the stronger antiestrogenic activity of its metabolites.

Lung neoplasia is a major cause of death in cancer patients throughout the world. Diagnostic techniques and therapeutic modalities for lung cancer patients have been improved over the past decade; however, the overall death rate is still high. 1) Despite undergoing curative surgical treatment, many patients develop recurrent disease and most of such recurrent disease includes distant metastasis.2, 3) Therefore, controlling metastatic disease is one of the important problems that must be addressed in order to conquer lung neoplasia.Among the various clinicopathological factors, lymphatic metastasis is one of the most critical factors for the prognosis of lung cancer patients. [4][5][6] Although experimental models for lung cancer have been reported by several investigators, these models have included some important drawbacks, such as ectopic implantations and complicated procedures.7-9) Recently, we established a model of spontaneous lymphatic metastasis produced by orthotopic implantation of lung cancer cells.10) Direct implantation of Lewis lung carcinoma (LLC) admixed with "MATRIGEL" into the left lobe of the lung caused the formation of a solitary tumor followed by metastasis to the mediastinal lymph node. This model should be useful for investigating therapeutic approaches for lung cancer disease in preclinical studies.We have reported that 4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid, TAC-101, abolished activating protein-1 (AP-1) binding to consensus DNA and inhibited the experimental liver metastasis of gastrointestinal tract cancer in animal models.11) AP-1 has been reported to be a major transcriptional enhancer for the expression of urokinase-type plasminogen activator, overexpression of which has been reported to be correlated with lymphatic metastasis of lung cancer. [12][13][14][15][16] In the present study, we investigated the effects of TAC-101 on the growth at the implantation site and the spontaneous lymphatic metastasis caused by the orthotopic implantation of LLC, and we examined its anti-metastatic mechanism of action in vitro. Since platinum agents have been used as standard treatment modalities for lung cancer, 1,17,18) combination therapy of TAC-101 and CDDP in the LLC model was also examined.

The present preclinical study was designed to evaluate a new combination therapy comprised of the aromatase inhibitor anastrozole (ANA) and the oral fluoropyrimidines, UFT and S-1 against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7/Arom 14, which was stably transfected with the cDNA of human aromatase. MCF-7/Arom 14 cells showed a high aromatase activity and notably were able to grow in the presence of testosterone and estradiol (E(2)) in vitro. ANA and 5-fluorouracil (5-FU) inhibited cell growth at concentrations of 0.005-10 and 0.2-5 μM, respectively, and the combination of both drugs additively inhibited cell growth. The growth of MCF-7/Arom 14 tumors was significantly inhibited by ANA and S-1 or UFT in vivo. The combination of ANA with S-1 or UFT administered using a 21-day consecutive, metronomic-like regimen significantly enhanced the antitumor efficacy, suppressing tumor growth for 2-4 times longer than monotherapy. To investigate the mechanisms by which S-1 enhances the antitumor activity of ANA, the protein and mRNA expression levels of ER-α in tumor tissue after treatment with S-1, ANA, and the typical chemotherapeutic agents doxorubicin (ADM) or paclitaxel (TXL) were analyzed. The protein and mRNA expression levels of ER-α in the tumor tissue were markedly decreased after treatment with S-1 or S-1 + ANA, but not after treatment with either ADM or TXL. The reduced ER-α level after S-1 treatment might contribute to the increased antitumor activity of ANA by reducing ER-α-induced growth signaling in addition to the decrease in estrogen production induced by ANA. Based on these results, the combination of ANA and S-1 might yield a greater benefit than other chemotherapeutic agents in postmenopausal women with ER-positive breast cancer.