[Two Cases of Unresectable/Advanced Breast Cancer with Pathological Complete Response after Combination Chemotherapy with Pertuzumab. Trastuzumab, and Docetaxel].

Combination chemotherapy with pertuzumab, trastuzumab, and docetaxel is recommended as the first-line treatment for patients with HER2-positive unresectable or metastatic breast cancer. We report 2 cases of unresectable breast cancer for which pertuzumab, trastuzumab, and docetaxel therapy was effective. Case 1: A woman in her 40s was diagnosed with TxN3aM0, Stage ⅢC, HER2-positive, hormone receptor-positive advanced breast cancer. After administration of 6 courses of pertuzumab, trastuzumab, and docetaxel therapy, she underwent surgery(Bt+Ax[Ⅱ]). Histopathological examination revealed that chemotherapy effect was Grade 3. Case 2: A woman in her 60s was diagnosed with de novo Stage Ⅳ, HER2- positive, hormone receptor-negative breast cancer. She was administered 8 courses of pertuzumab, trastuzumab, and docetaxel therapy as the third-line treatment, because she initially refused treatment. Thereafter, she underwent surgery(Bt+Ax [Ⅰ]). In both cases, histopathological examination revealed complete response after chemotherapy. Thus, combination therapy of pertuzumab and trastuzumab may improve the prognosis in patients with HER2-positive breast cancer.

Mechanism for the regulation of mammalian cGMP phosphodiesterase6. 2: isolation and characterization of the transducin-activated form.

Rod photoreceptor cGMP phosphodiesterase (PDE6) consists of a catalytic subunit complex (Palphabeta) and two inhibitory subunits (Pgamma). In the accompanying article, using bovine photoreceptor outer segment homogenates, we show that Pgamma as a complex with the GTP-bound transducin alpha subunit (GTP-Talpha) dissociates from Palphabetagammagamma on membranes, and the Palphabetagammagamma becomes Pgamma-depleted. Here, we identify and characterize the Pgamma-depleted PDE. After incubation with or without guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS), Palphabeta complexes are extracted. When a hypotonic buffer is used, Palphabetagammagamma, Palphabetagamma, and a negligible amount of a Palphabeta complex containing Pgamma are isolated with GTPgammaS, and only Palphabetagammagamma is obtained without GTPgammaS. When an isotonic buffer containing Pdelta, a prenyl-binding protein, is used, Palphabetagammagammadelta, Palphabetagammadeltadelta, and a negligible amount of a Palphabeta complex containing Pgamma and Pdelta are isolated with GTPgammaS, and Palphabetagammagammadelta is obtained without GTPgammaS. Neither Palphabeta nor Palphabetagammagamma complexed with GTPgammaS-Talpha is found under any condition we examined. Palphabetagamma has approximately 12 times higher PDE activity and approximately 30 times higher Pgamma sensitivity than those of Palphabetagammagamma. These results indicate that the Pgamma-depleted PDE is Palphabetagamma. Isolation of Palphabetagammagammadelta and Palphabetagammadeltadelta suggests that one C-terminus of Palphabeta is involved in the Palphabetagammagamma interaction with membranes, and that Pgamma dissociation opens another C-terminus for Pdelta binding, which may lead to the expression of high PDE activity. Cone PDE behaves similarly to rod PDE in the anion exchange column chromatography. We conclude that the mechanisms for PDE activation are similar in mammalian and amphibian photoreceptors as well as in rods and cones.

Mechanism for the regulation of mammalian cGMP phosphodiesterase6. 1: identification of its inhibitory subunit complexes and their roles.

Cyclic GMP phosphodiesterase (PDE) in bovine rod photoreceptor outer segments (OS) comprises a catalytic subunit complex (Palphabeta) and two inhibitory subunits (Pgamma) and is regulated by the alpha subunit of transducin (Talpha). Here, we show an overall mechanism for PDE regulation by identifying Pgamma complexes in OS homogenates prepared with an isotonic buffer. Before Talpha activation, three Pgamma complexes exist in the soluble fraction. Complex a, a minor complex, contains Palphabeta, Talpha, and a protein named Pdelta. Complex b, Palphabetagammagamma( b ), has a PDE activity similar to that of membranous Palphabetagammagamma, Palphabetagammagamma( M ), and its level, although its large portion is Pdelta-free, is estimated to be 20-30% of the total Palphabetagammagamma. Complex c, (Pgamma.GDP-Talpha) (2) ( c ) , appears to be a dimer of Pgamma.GDP-Talpha. Upon Talpha activation, (1) complex a stays unchanged, (2) Palphabetagammagamma( b ) binds to membranes, (3) the level of (Pgamma.GDP-Talpha) (2) ( c ) is reduced as its GTP-form is produced, (4) complex d, Pgamma.GTP-Talpha( d ), is formed on membranes and its substantial amount is released to the soluble fraction, and (5) membranous Palphabetagammagamma, Palphabetagammagamma( M ) and/or Palphabetagammagamma( b ), becomes Pgamma-depleted. These observations indicate that Pgamma as a complex with GTP-Talpha dissociates from Palphabetagammagamma on membranes and is released to the soluble fraction and that Pgamma-depleted PDE is the GTP-Talpha-activated PDE. After GTP hydrolysis, both (Pgamma.GDP-Talpha) (2) ( c ) and Pgamma.GDP-Talpha( d ), without liberating Pgamma, deactivate Pgamma-depleted PDE. The preferential order to be used for the deactivation is membranous Pgamma.GDP-Talpha( d ), solubilized Pgamma.GDP-Talpha( d ) and (Pgamma.GDP-Talpha) (2) ( c ) . Release of Pgamma.GTP-Talpha complexes to the soluble fraction is relevant to light adaptation.