(R)- and (S)-4-Amino-3-(trimethylsilyl)methylbutanoic acids ameliorate neuropathic pain without central nervous system-related side effects.

Neuropathic pain is a chronic pain condition resulting from neuronal damage, and is usually treated with pregabalin or gabapentin, which are structurally related to γ-aminobutyric acid (GABA) and are originally developed as anticonvulsant drugs. Here, we report the synthesis and pharmacology of (R)- and (S)-4-amino-3-(trimethylsilyl)methylbutanoic acids (1a and 1b), which showed analgesic activity as potent as that of pregabalin in the Chung spinal nerve ligation model. However, unlike pregabalin, 1a and 1b do not have antiepileptic effects, and they are therefore promising candidates for selective therapeutic agents to treat neuropathic pain without central nervous system-related side effects.

Phase I study of TAC-101, an oral synthetic retinoid, in Japanese patients with advanced hepatocellular carcinoma.

Preclinical models have shown that TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has antitumor activity in hepatocellular carcinoma (HCC). We conducted a phase I study in Japanese patients with advanced HCC to examine the pharmacokinetics, recommended dose, safety, and efficacy of TAC-101. The administered dose of TAC-101 was 10 mg/day in four patients (level 1), 20 mg/day in six (level 2), and 30 mg/day in three (level 3). There was no dose-limiting toxicity at level 1. Only one patient each had dose-limiting toxicity at level 2 (grade 2 fatigue, recovery requiring eight or more consecutive days of rest) and at level 3 (grade 3 splenic vein thrombosis). Level 3 (30 mg/day) was considered the maximum tolerated dose and 20 mg/day the recommended dose by a panel of medical experts, placing maximum emphasis on safety. The most frequent adverse events were fatigue, headache, and dermal symptoms such as rash. Pharmacokinetic parameters in Japanese patients with HCC were similar to those in patients in the United States, most of whom were Caucasian. Although no patient had a complete or partial response, the disease control rate was 38.5%. In conclusion, the recommended dose of TAC-101 for patients with HCC is 20 mg/day. TAC-101 had an acceptable toxicity profile, warranting further evaluation in clinical trials.

Chemopreventive effect of 4-[3,5-Bis(trimethylsilyl) benzamido] benzoic acid (TAC-101) on MNU-induced colon carcinogenesis in a rat model.

PURPOSE: 4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative. The chemopreventive effect and the mechanism of action of TAC-101 were investigated using a rat chemical colon carcinogenesis model. MATERIALS AND METHODS: Colon tumors were induced using intra-rectal instillation of N-methyl-N-nitrosourea (MNU) in F344 rats. These rats were divided into five groups, control, high dose (TAC-101 8 mg/kg)-long period (four weeks), high dose-short period (one week), low dose (TAC-101 0.8 mg/kg)-long period and low dose-short period. After the large bowels were resected at 20 weeks, the number of aberrant crypt foci (ACF) and tumors in the colon were counted. Proliferating cell nuclear antigen (PCNA) positive index, apoptotic index (AI) and Fas expression were also evaluated using immunohistochemistry. RESULTS: The tumor incidence and the tumor number in the high dose-long period group were decreased in comparison to those in the other groups, but not significantly. However, the number of ACF or PCNA positive indices in the high dose-long period group was significantly decreased in comparison to that in the other groups. On the other hand, the AI and the Fas expression pattern in the tumor and the normal appearing mucosa were not changed in any of the groups. CONCLUSION: TAC-101 might inhibit MNU induced colon carcinogenesis via a decrease of ACF. The mechanism of this chemoprevention may be related to a reduction in cell proliferation, but is not directly associated with apoptosis.

A synthetic retinoid Am80 (tamibarotene) rescues the memory deficit caused by scopolamine in a passive avoidance paradigm.

Memory deficit in rats treated with scopolamine was rescued by several synthetic retinoids, RAR-ligands (Am80, Am555S, Tp80) and an RXR-ligand (HX630). These results may have implications for the treatment of Alzheimer's disease, age-related dementia, Parkinson's disease, and other neurological disorders.

4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor.

4-[3,5-bis(trimethylsilyl)benzamido] Benzoic acid (TAC-101) has potent antiproliferative, antiangiogenic, and antitumor effects in vitro and in vivo. These effects might be due to TAC-101 binding to retinoic acid receptor alpha (RAR-alpha) and interfering with the binding of activator protein-1 (AP-1) to DNA. However, little is known about the detailed mechanism of TAC-101 function. We investigated the mechanism of the antiangiogenic effect of TAC-101 using a rat hepatic metastatic model in vivo and DLD-1 human colon cancer cells in vitro. Liver metastases were induced by portal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 (8 mg/kg) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density (MVD) and vascular endothelial growth factor (VEGF). TAC-101 significantly reduced both MVD and VEGF expression. Northern blot analysis and ELISA indicated that TAC-101 efficiently inhibited production of VEGF mRNA and protein in DLD-1 cells in a time- and dose-dependent manner. These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF.

Effect of synthetic retinoid, TAC-101, on experimental autoimmune disease.

The effect of 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid (TAC-101), one of the synthetic retinoids, on collagen-induced arthritis (CIA) in mice and experimental autoimmune encephalomyelitis (EAE) in rats was studied. TAC-101 at doses of 5 and 20 mg/kg clearly inhibited the development of CIA in terms of the swelling of fore- and hind-limbs and bone destruction in knee joints. TAC-101 also suppressed the production of anti-type II collagen (CII) IgG antibody and delayed-type hypersensitivity (DTH) against CII. In addition, TAC-101 delayed the onset and development of EAE but did not affect the maximum symptom of EAE in rats. The elevation of serum antimyelin basic protein (MBP) antibody and DTH to MBP on day 13 clearly suppressed by TAC-101 in EAE rats. Moreover, TAC-101 inhibited the IL-1beta-induced PGE(2) production by MG-63 cells, human osteoblast-like cells, through the suppression of cyclooxygenase II mRNA expression. These findings suggest that TAC-101 inhibits CIA in mice and EAE in rats due to the suppression of immune response to auto-antigen and the production of PGE(2).

A potential use of a synthetic retinoid TAC-101 as an orally active agent that blocks angiogenesis in liver metastases of human stomach cancer cells.

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a novel, synthetic retinoid that is effective against liver metastases of human gastrointestinal cancer cells such as the human stomach carcinoma line AZ-521 in animal models, and is currently in use in phase I cancer trials. However, the mechanism of its antimetastatic action is still poorly understood. Tumor metastasis depends on angiogenesis, and various retinoids have been found to exhibit antiangiogenic activity. Based on these findings we here examined the antiangiogenic effects of TAC-101. Oral administration of TAC-101 (2-8 mg/kg/day) resulted in a drastic suppression of the AZ-521 cell-induced angiogenesis in a mouse dorsal air sac assay system, compared to the vehicle alone. Immunohistochemical analysis with antibody against the endothelial marker CD31 revealed a significant reduction in microvessel density in liver metastases from animals treated with TAC-101 (8 mg/kg p.o.), compared to liver metastases from the untreated control animals. The ability of TAC-101 (8 mg/kg p.o.) to prevent experimental liver metastasis of AZ-521 cells in athymic nude mice was comparable with that of the known angiogenesis inhibitor TNP-470 (30 mg/kg s.c.). TAC-101 also affected angiogenesis in chorioallantoic membranes and some functions of endothelial cells associated with angiogenesis, whereas the retinoid failed to suppress AZ-521 cell proliferation directly. These data suggest that the TAC-101 is an orally active antiangiogenic agent and that this antiangiogenic property may contribute to its efficacy against liver metastasis of human stomach cancer cells.

Anticancer effect of 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) against A549 non-small cell lung cancer cell line is related to its anti-invasive activity.

We examined the effects of TAC-101 on the invasion and metastasis of human non-small cell lung cancer (NSCLC) cell lines. TAC-101 showed an ability to inhibit in vitro invasiveness of NSCLC at a non-cytotoxic concentration range of 3-10 microM; such concentration levels were easily achievable following oral administration of therapeutically effective doses. The inhibition of cell invasion at 10 microM of TAC-101 accounted for 58-69% when compared with control cells. Oral administration of TAC-101 (4 mg/kg/day) to mice bearing lung implanted A549 lung cancer resulted in significant life-prolonging effect (T/C: 143%). More pronounced life-prolonging effect was observed in the experimental liver metastasis model of A549, where T/C of 215% was observed following administration at 4 mg/kg/day of TAC-101. However, TAC-101 did not show the direct anti-tumor effect against the established A549 tumor xenografts after subcutaneous implantation. These findings suggest that TAC-101 interferes with cell-to-cell interaction processes leading, for instance, to the inhibition of the invasion of NSCLC cells. Taking into account the pharmacological properties of TAC-101, it is expected that TAC-101 may be a suitable candidate drug for the treatment of lung cancer patients, especially those with a predictable metastasizing potential.

Effect of 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) on the liver metastasis of colon 26-L5 carcinoma cells.

We found that oral administration of the benzoic acid derivative, TAC-101 ¿4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid¿ significantly inhibited experimental liver metastasis of murine colon 26-L5 carcinoma cells, whereas all-trans-retinoic acid (ATRA) did not show any inhibitory effect. Treatment with more than 10 microM TAC-101 for 24 h showed direct cytotoxicity against tumor cells in vitro. In contrast, ATRA did not have any direct cytotoxicity. TAC-101 also inhibited the tumor cell invasion enhanced by TPA (12-O-tetradecanoylphorbol-13-acetate; AP-1 activator) in a concentration-dependent manner, whereas ATRA did not. Furthermore, zymographic analysis revealed that noncytotoxic concentrations (< 10 microM) of TAC-101 inhibited TPA-induced production of urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase (MMP)-9 from tumor cells, which is considered to be associated with their invasive and metastatic potentials. These results suggest that such an inhibitory effect is partly due to the ability of TAC-101 to bind a retinoic acid receptor (RAR)-alpha and consequently inhibit metastasis-related gene transcription by interfering with AP-1/DNA binding, as we showed previously. On the other hand, TAC-101 also inhibited the production of MMP-2, which is not affected by TPA. Therefore, the antimetastatic effect of TAC-101 includes an alternative regulatory mechanism for MMP production. These results indicate that the in vivo antimetastatic effect of TAC-101 is partly due to the cytotoxicity against tumor cells, which may be caused by the induction of apoptosis, and inhibition of the production of invasion-associated proteolytic enzymes.

TAC-101, a benzoic acid derivative, inhibits liver metastasis of human gastrointestinal cancer and prolongs the life-span.

We examined the anti-tumor effect of a novel benzoic acid derivative, TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid) on models with liver metastasis. Oral administration of TAC-101 significantly inhibited spontaneous liver metastasis of AZ-521 (human gastric cancer ) by orthotopic implantation to athymic nude mice. It also inhibited both the liver metastasis of AZ-521 induced by intrasplenic injection and the secondary lung metastasis from the liver. In addition, TAC-101 inhibited the proliferation of Co-3 (human colon adenocarcinoma) that formed a single nodule in the liver of athymic nude mice by intrahepatic implantation. The growth inhibitory effect of TAC-101 on AZ-521 experimental liver metastasis was observed when treatment was started on day 7, 14, or 21 which may correspond to the progressive stage of liver metastasis in clinical settings. Multiple administration of TAC-101 (8 mg/kg/day) significantly prolonged survival time of the animals with liver metastasis by intrasplenic injection of AZ-521 (T/C = 230%) and A549 (human lung adenocarcinoma; T/C = 186%). These effects of TAC-101 were stronger than those of 5-FU, CDDP or ATRA. Furthermore, TAC-101 inhibited the binding of AP-1 to DNA on electrophoretic mobility shift assay using nuclear extract of AZ-521 cells, although ATRA did not inhibit. These findings suggested that TAC-101 may be a candidate for a new class of anti-cancer agents for liver metastasis.

[Control of tumor-related angiogenesis].

Tumor-related angiogenes is expected to become an important target for improving treatment of cancer, because it plays key roles in tumor growth, invasion and metastasis. We considered that the successful development of such angiostatic treatment depended entirely upon the development of useful anti-angiogenic agents, and attempted to find novel angiogenesis inhibitors by using three in vivo assays, based on an idea of ours. As a result we have demonstrated that different types of agents with low molecular weight including microbial metabolites, cell differentiation modulators like retinoids and steroids, exhibit anti-angiogenic activity, anti-metastatic activity and/or antitumor activity. Taken these findings, an ideal anti-angiogenic agent is discussed.

Retinobenzoic acids. 5. Retinoidal activities of compounds having a trimethylsilyl or trimethylgermyl group(s) in human promyelocytic leukemia cells HL-60.

The retinoidal activities of trimethylsilyl or trimethylgermyl-containing retinobenzoic acids are discussed on the basis of differentiation-inducing activity on human promyelocytic leukemia cells HL-60. Compounds with a trimethylsilyl or trimethylgermyl group at the meta position of the generic formula 2 have more potent activities than the corresponding retinobenzoic acids with a m-tert-butyl group. Compounds having two m-trimethylsilyl or -trimethylgermyl groups also have strong activities, and (E)-4-[3-[3,5-bis(trimethylsilyl)phenyl]-3-oxo-1-propenyl]benzoic acid (22, Ch55S) and (E)-4-[3-[3,5-bis(trimethylgermyl)phenyl]-3-oxo-1- propenyl]benzoic acid (35, Ch55G) are more active than retinoic acid by 1 order of magnitude. However, in the para-substituted chalcone derivatives, the replacement of a tert-butyl group (49, Ch40) with a trimethylsilyl (27, Ch40S) or a trimethylgermyl (30, Ch40G) group caused the disappearance of the activity.

[Mercaptopurine and silylated mercaptopurine the treatment of experimental allergic encephalomyelitis]. / Mercaptopurin und silyliertes Mercaptopurin in der Behandlung der experimentell allergischen Enzephalomyelitis.

The therapeutic effects of mercaptopurine (6-mercaptopurine, 6-MP) and a silylated derivative (6-trimethylsilylthio-9-trimethyl-silylpurine, S-MP) were compared on the course of T lymphocyte line mediated experimental allergic encephalomyelitis (t-EAE). This transferred EAE is a passively induced model disease in Lewis rats easy to elicit, reliably reproducible and characterized by a dose-dependent lethality. If given at different points in single injections the silicon derivative is shown to be more efficient than 6-MP (43/125 surviving animals compared to 26/129), severity of disease is attenuated and number of survivors increased. Silylation is able to improve blood-brain barrier and cellular permeability; S-MP suppresses intrathecal inflammatory cells more effectively than the original immunosuppressant.

[Combination chemotherapy of multiple myeloma--BCNU.cyclophosphamide.procarbazine.prednisolone and MCNU.cyclophosphamide.procarbazine.prednisolone therapy].

Forty-four patients with progressive symptomatic multiple myeloma were treated with a protocol combining cyclophosphamide (10 mg/kg weekly), procarbazine (2 mg/kg daily), prednisolone (20 mg daily), and either BCNU (1 mg/kg weekly) (BCPP protocol) or MCNU (0.8-1 mg/kg) (MCPP protocol). Of these, 34 patients were treated with the former, and 10 patients with the latter. With BCPP protocol, 12 achieved a complete response, 11 evidenced a 75% response, and 7 displayed a 50% response. With MCPP protocol, on the other hand 2 achieved a complete response, 6 showed a 75% response, and 1 exhibited a 50% response. The median tumor halving time in both groups was 77 days and 57 days respectively. The 5-yr disease-free survival of patients treated with BCPP protocol was 62.0 +/- 10.8%. In MCPP group, 8 of 10 patients are alive with more than 49-87 weeks survival. Although myelotoxicity was moderate, other toxicities were moderate. Toxicity requiring dose modification and discontinuation of the scheduled therapy was observed.

[Synthesis and study of 5-(trialkylsilyl)pyrimidine nucleosides. A new alpha-2'-deoxynucleoside with antiherpes activity]. / Sintez i izuchenie 5-(trialkilsilil)pirimidinovykh nukleozidov. Novyi alpha-2'-dezoksinukleozid s antigerpeticheskoi aktivnost'iu.

Glycosylation of 5-trimethylsilyl- and 5-triethylsilyluracil as well as 5-trimethylsilylcytosine with 2-deoxy-3,5-di-O-p-toluyl-alpha-D-ribofuranosylchloride and subsequent deacylation led to alpha- and beta-anomers of 5-Me3SidUrd, 5-Et3SidUrd and 5-Me3SidCyd. 1-(alpha-D-Arabinofuranosyl)-5-trimethylsilyluracil was synthesized starting from the derivatives of 2,3,5-tri-O-benzoyl-D-arabinofuranose and then converted to alpha-5-Me3SidUrd via 1-(2,2'-anhydro-alpha-D-ribofuranosyl)-5-trimethylsilyluracil and 1-(2-chloro-2-deoxy-alpha-D-arabinofuranosyl)-5-trimethylsilyluracil+ ++. Out of all synthesized compounds, only alpha-5-Me3SidUrd inhibits the replication of HSV-1 both in vitro and in vivo; it also exerts a pronounced therapeutic effect in guinea pigs with herpes genitalis induced by HSV-2. The resistance of alpha-5-Me3SidUrd to pyrimidine phosphorylases facilitates its antiviral activity in vivo.