[A case of trastuzumab-resistant breast cancer responding to lapatinib/capecitabine therapy].

Here we report a case of a 56-year-old woman who presented at our hospital with a chief complaint of a red lump in her right breast. Breast cancer(Rt C, T4bN0M0; ER[-], PgR[-], HER2: 3[+]; stage IIIb)was diagnosed, and subsequent preoperative chemotherapy, mastectomy and axillary lymph node dissection were performed. Five months after surgery, bone metastasis in the thoracolumbar vertebrae developed and trastuzumab/zoledronic acid hydrate therapy was initiated. Four months after the therapy, tumor marker levels increased and docetaxel was added to the treatment regimen. Although the patient's condition temporarily improved, tumor marker levels increased again after 6 months, and the treatment regimen was switched to trastuzumab/nab-paclitaxel therapy. However, such regimen was discontinued owing to the development of liver metastasis, and lapatinib/capecitabine therapy was initiated. Two months after lapatinib/capecitabine therapy, tumor marker levels normalized and the liver metastasis markedly reduced. Side effects included paronychia(grade 3), which improved with dose reduction. The patient's therapy is being continued.

Synthesis and biological evaluation of tubulysin D analogs related to stereoisomers of tubuvaline.

The synthesis and biological evaluation of stereoisomers in tubulysin D are described. The stereoselective synthesis of all possible stereoisomers of C-11 and C-13 positions in tubulysin D was achieved by employing 1'-epi-Tuv-Me, 3'-epi-Tuv-Me, and ent-Tuv-Me and their biological properties were evaluated. It is clear that the stereochemistries of the C-11 and C-13 positions in tubulysin D have no practical impact on the inhibition of tubulin polymerization but play a role in the potent antiproliferative activities.

Total syntheses of tubulysins.

The total syntheses of tetrapeptides tubulysins D (1 b), U (1 c), and V (1 d), which are potent tubulin polymerization inhibitors, are described. The synthesis of Tuv (2), an unusual amino acid constituent of tubulysins, includes an 1,3-dipolar cycloaddition reaction of chiral nitrone D-6 derived from D-gulose with N-acryloyl camphor sultam (-)-9 employing the double asymmetric induction, whereas the synthesis of Tup (20), another unusual amino acid, involves a stereoselective Evans aldol reaction of (Z)-boron enolate generated from (S)-4-isopropyl-3-propionyl-2-oxazolidinone with N-protected phenylalaninal and a subsequent Barton deoxygenation protocol. We accomplished the total syntheses of tubulysins U (1 c) and V (1 d) by using these methodologies, in which the isoxazolidine ring was used as the effective protective group for γ-amido alcohol functionality. Furthermore, to understand the structure-activity relationship of tubulysins, we synthesized tubulysin D (1 b) and cyclo-tubulysin D (1 e) from 2-Me and 20, and ent-tubulysin D (ent-1 d) from ent-2-Me and ent-20, respectively. The preliminary results regarding their biological activities are also reported.

Oleamide derivatives suppress the spontaneous metastasis by inhibiting connexin 26.

We previously reported that overexpressing connexin 26 (Cx26) enhances the spontaneous metastasis of mouse BL6 melanoma cells. In contrast, daily intraperitoneal injections of an oleamide derivative named MI-18 potently inhibits the spontaneous metastasis of BL6 cells. In the present study, we chemically synthesized a novel oleamide derivative named MI-22 and found that it also efficiently suppressed the spontaneous metastasis of BL6 cells. Both MI-18 and MI-22 inhibited the gap junction-mediated intercellular communications (GJIC) that are formed between HeLa cells by the ectopic expression of the hCx26 and hCx32 human connexin subtypes; however, they had no effect on GJIC mediated by hCx40, hCx43 or hCx45. Fluorescently labeled MI-18 primarily localized not only at plasma membrane but also at Golgi/endosome. This suggests that this oleamide derivative may also act on the Cx26 molecules that accumulate in the Golgi/endosome because of their overexpression. Notably, neither derivative had a cytotoxic effect on HeLa cells when they were added into the tissue culture medium. Taken together, we propose that the MI-18 and MI-22 oleamide derivatives may serve as prototypes for novel and clinically important anticancer drugs.

A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells.

We reported previously that the abnormally augmented expression of connexin 26 (Cx26) is responsible for the enhanced spontaneous metastasis of mouse BL6 melanoma cells, and that the exogenous expression of a dominant negative form of Cx26 inhibits the spontaneous metastasis of BL6. Here we show that daily intraperitoneal (i.p.) injections of oleamide, a sleep-inducing lipid hormone, weakly inhibited the spontaneous metastasis of BL6 cells. To obtain a more effective reagent, 19 oleamide derivatives were chemically synthesized and tested for their ability to inhibit the gap junction-mediated intercellular communications (GJIC) that are formed between HeLa cells by the ectopic expression of Cx26 or Cx43. One of these, denoted metastasis inhibitor-18 (MI-18), inhibited the GJIC formed by Cx26 as well as oleamide but unlike oleamide, which is a non-selective inhibitor of connexin, it did not inhibit the GJIC formed by Cx43. Daily i.p. injections of MI-18 potently blocked the spontaneous metastasis of BL6 cells down to 15% of that in the untreated control mice. MI-18 was safe because even after >7 weeks of daily injections, the survival rate of the mice was 93%. We propose that MI-18 may serve as a novel and clinically important prototype of a potent inhibitor of spontaneous metastasis.

[A case of gastric cancer with multiple liver metastases responding completely to TS-1].

We report a case of a 65-year-old male with stage IV gastric cancer accompanied by liver metastases, which showed a significant response after administration of TS-1. One hundred and twenty mg/body/day of TS-1 was orally administered without hospitalization. After 3 months, upper GI endoscopy showed improvement of primary gastric lesion, and cancer cells could not be detected under biopsy. After 2 months, computed tomography (CT) showed a reduction in the multiple liver metastases. Moreover, after 15 months, CT showed a complete regression of the multiple liver metastases, for a complete response (CR). The serum level of carcinoembryonic antigen (CEA) was reduced from 115 to within normal range. Noticeable critical adverse effects did not appear. Treatment on an outpatient basis, therefore, greatly contributed to his quality of life. We judged that TS-1 might be a candidate anti-cancer drug for first-line chemotherapy for advanced gastric cancer.