[Left ventricular-right atrial communication resulting from infective endocarditis].

We report a rare case of acquired left ventricular-right atrial communication resulting from infective endocarditis. A 57-year-old male with aortic regurgitation due to infective endocarditis was referred to our hospital because of severe congestive heart failure. Preoperative transthoracic echocardiography showed aortic, mitral and tricuspid severe regurgitations. Intraoperative transesophageal echocardiography revealed left ventricular-right atrial shunt. The fistula was located at the atrioventricular membranous septum. The communication site from the left view was below the commissure between the right coronary cusp and non-coronary cusp, and from the right view was just above the tricuspid annulus of the septal leaflet. The fistula was closed directly with mattress suture and aortic valve replacement and both mitral and tricuspid ring annuloplasty were carried out simultaneously. The postoperative course was uneventful. It is important to inspect shunts carefully in echocardiography of infective endocarditis with massive regurgitations.

Enhanced tumor cell selectivity of adriamycin-monoclonal antibody conjugate via a poly(ethylene glycol)-based cleavable linker.

A novel linker consisting of poly(ethylene glycol) (PEG) and dipeptide was used for conjugation of adriamycin with tumor-specific monoclonal antibody, NL-1, to confirm that the linker can be cleaved selectively with the tumor specific enzyme to express cytotoxicity of the anti-tumor agent. Initially, adriamycin-conjugated PEG linkers through different amino acid compositions, alanyl-valine (Ala-Val), alanyl-proline (Ala-Pro), and glycyl-proline (Gly-Pro) sequences, were prepared to confirm selective digestion with model enzymes. Adriamycin was released by particular model endoproteases, thermolysin and proline endopeptidase, from the linkers with different efficiency. When conjugates were prepared using these adriamycin-bound linkers, conjugates had no loss of binding affinity and specificity for common acute lymphoblastic leukemia antigen (CALLA) expressed on the Daudi cell surfaces as the target of NL-1 antibody. In addition, adriamycin release from the conjugates was also confirmed by incubating them with specific proteases. Tumor cell growth was inhibited dose-dependently for the conjugates carrying Ala-Val and Gly-Pro linkers, whereas significant inhibitory effect was abolished for the conjugate carrying Ala-Pro linker, indicating that cytotoxic effect can be controlled by specificity of antibody and composition of linker peptide. IC(50) for Ala-Val linked conjugate was approximately 3.5 microg/ml and that for Gly-Pro linked conjugate was 5.2 microg/ml. PEG-dipeptidyl linker demonstrated here will be an effective tool for the preparation of immunoconjugate, especially specific activation of anti-tumor agents at desired tumor tissues.

[Properties of antitumor activity of vinorelbine tartrate, a new vinca alkaloid antitumor agent].

Vinorelbine (VNR) is a new vinca alkaloid derivative semi-synthesized by Potier et al. The antitumor activity of VNR was superior to other vinca alkaloid antitumor agents, and the neuro-toxicity of VNR was weaker than those of other vinca alkaloids. In nude mice xenografted human tumor models, VNR showed antitumor activity against eight of eleven tumor models (non-small cell lung cancer: 4/4, breast cancer: 2/3, colon cancer: 0/2, stomach cancer: 2/2). Especially, VNR showed tumor-regressive activity against LC-6 non-small cell lung cancer and MX-1 breast cancer. The antitumor activity of VNR against non-small cell lung cancer was superior to that of vindesine (VDS), which had been one of the key drugs of non-small cell lung cancer in the clinic. In combination chemotherapy, VNR plus cisplatin (CDDP) was better than VDS plus CDDP, which had been one of the standard regimens of non-small cell lung cancer chemotherapy. The potent antitumor effect of VNR with minor neurotoxicity was explained by VNR having stronger activity on mitotic microtubules than axonal microtubules. It was supposed that less activity of VNR against mitotic microtubules would be related to different composition of microtubule-associated TAU isoforms in the two types of microtubules. In non-small cell lung cancer, VNR resulted in a significantly higher response rate than VDS. In combination with CDDP, VNR resulted in longer survival than VDS with a significant log-rank test. In advanced breast cancer, VNR resulted in a high response rate in 1st line and 2nd line treatment. VNR is effective in combination with chemotherapeutic agents such as anthracycline, fluorouracil and Taxol. In Japan, the clinical trial in breast cancer is now ongoing.

Therapeutic potential of chimeric anti-(ganglioside GD3) antibody KM871: antitumor activity in xenograft model of melanoma and effector function analysis.

KM871 is a chimeric antibody recognizing ganglioside GD3, which is one of the major gangliosides expressed on the cell surface of human tumors of neuroectodermal origin. This study demonstrates the antitumor activity of KM871 against human melanoma xenografts in nude mice, and analyzes the effector function operating in mice. In a well-established tumor model, KM871 showed antitumor activity against H-15 and SK-MEL-28 human melanoma but not against H-187 and G361 human melanoma when administered intravenously 5 days/week for 2 weeks. The G361 tumor became sensitive when KM871 was first administered on the day of tumor inoculation. In this assay, it was observed that almost all the mice were tumor-free, but a few mice developed tumors. Therefore, we examined the amount and expression pattern of GD3 antigen on G361 tumors escaping from KM871 treatment, but no change was observed. Next we examined the optimal administration schedule for KM871 in mice, using H-15 melanoma. KM871 showed antitumor activity when administered intravenously either 5 days/week for 2 weeks or three biweekly doses. However, the effect of the former schedule was stronger than three biweekly doses. To compare the effector function in humans and mice, we studied the complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent macrophage-mediated cytotoxicity of KM871 using complement or effector cells prepared from humans and mice. It was found that the antibody-dependent cell-mediated cytotoxicity exerted by polymorphonuclear cells and antibody-dependent macrophage-mediated cytotoxicity were the only antitumor mechanism of KM871 in mice. However their action was very weak compared with that in humans, and complement-mediated cytotoxicity, which was strong in humans, was not observed in mice. Therefore, the antitumor activity of KM871 against human melanomas evaluated by the nude mouse model might be underestimated. These results indicate that KM871 shows good antitumor activity against GD3-positive human melanoma and the antitumor activity expected in humans might be superior to that of the nude mouse model.

Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration.

UNLABELLED: 2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine (Cl-F-araA) is a novel deoxyadenosine analog, which inhibits DNA synthesis by inhibiting DNA polymerase alpha and ribonucleotide reductase. Cl-F-araA shows potent antiproliferative activity against several leukemic cell lines including those of human origin and is also effective against murine solid tumors, in particular being curative against colon tumors. PURPOSE: We therefore decided to investigate whether Cl-F-araA is effective against human colon tumors, in particular by oral administration, since it has improved stability compared with other deoxyadenosine analogs. METHODS: Antiproliferative activity in vitro was determined from cell counts. Subcutaneously inoculated xenograft models and a liver micrometastases model were used for assessment of antitumor activity in vivo. RESULTS: Cl-F-araA showed potent antiproliferative activity against four human colon tumor cell lines (HCT116, HT-29, DLD-1, WiDr), with a 50% growth-inhibitory concentration (IC50) of 0.26 microM with a 72-h exposure. This activity was greater than those of fludarabine desphosphate and cladribine, other deoxyadenosine analogs, which showed IC50 values of 19 microM and 0.35 microM, respectively. Cl-F-araA showed potent antitumor activity against four human colon tumor xenograft models (HT-29, WiDr, Co-3, COLO-320DM) in a 5-day daily administration schedule, which was shown to be the most effective of three administration regimens tested (single, twice-weekly, 5-day daily). In particular, oral administration showed significantly superior activity, with a regressive or cytostatic growth curve, compared with intravenous administration. In addition, Cl-F-araA was effective at only one-sixteenth of the maximum dose tested in a 10-day daily administration schedule. Therapeutic efficiency seemed to increase in proportion to the frequency of administration. Cl-F-araA also decreased liver micrometastases created by intrasplenic injection of human colon tumor cells, leading to complete suppression at the maximum dose tested. CONCLUSIONS: These results suggest that Cl-F-araA might be clinically effective against human colon cancers using a daily oral administration schedule.

The relationship between the antitumor activity and the ribonucleotide reductase inhibitory activity of (E)-2'-deoxy-2'-(fluoromethylene) cytidine, MDL 101,731.

(E)-2'-deoxy-2'-(fluoromethylene) cytidine (MDL101,731) is a new deoxycytidine analog which shows potent antitumor activity against several human tumor models. We previously showed that MDL101,731 inhibited human ribonucleotide reductase (RNR) in HeLa S3 human cervical carcinoma cells. Recently, it has been reported that another deoxycytidine analog, 2'-deoxy-2'-methylidenecytidine (DMDC) which also inhibits RNR from Escherichia coli, does not inhibit RNR in intact L1210 murine leukemia cells. MDL101,731 was designed as an inhibitor of RNR, so it is important to know the contribution of the RNR inhibitory activity of the drug on its antitumor efficacy in vivo. Therefore, we examined the relationship between the antitumor activity and RNR inhibitory activity of MDL101,731 using LX-1 human lung carcinoma which was highly sensitive to this drug. MDL101,731 showed strong inhibition of RNR activity in LX-1 lung carcinoma by both i.v. and p.o. administration. Administration of 15 mg/kg i.v. and 30 mg/kg p.o. of MDL101,731, doses which showed almost the same degree of antitumor activity against LX-1 lung carcinoma on a daily 5 day schedule, caused a similar degree and similar kinetics of inhibition of RNR in LX-1 lung carcinoma at least for 12 h after administration. On the other hand, DMDC as well as 1-beta-D-arabinofuranosyl-cytosine (ara-C), which is a well-known deoxycytidine analog and inhibits DNA polymerase alpha, did not inhibit RNR in LX-1 lung carcinoma at doses demonstrating antitumor activity. These results indicate that MDL101,731 exhibited antitumor activity through inhibition of RNR activity in tumor cells in vivo and the mechanism of antitumor action of MDL 101,731 might be different from those of DMDC and ara-C, at least in part.

Metabolism and ribonucleotide reductase inhibition of (E)-2'-deoxy-2'-(fluoromethylene)cytidine, MDL 101,731, in human cervical carcinoma HeLa S3 cells.

UNLABELLED: (E)-2'-Deoxy-2'-(fluoromethylene)cytidine, MDL 101,731, has shown potent antitumor activity against various human xenograft models. PURPOSE: The purpose of this study was to elucidate the mechanism of the antitumor activity of MDL 101,731 against human carcinoma cells through investigating metabolism and the target enzyme of MDL 101,731. METHODS: In respect of the intracellular metabolism of MDL 101,731, the effect on enzymes in the pyrimidine salvage pathway and the intracellular metabolites of MDL 101,731 were investigated. In respect of the target enzyme, the effect on intracellular deoxyribonucleoside triphosphate (dNTP) pools and the inhibition of the enzyme activity were investigated. RESULTS: MDL 101,731 which shows antiproliferative activity against human cervical carcinoma HeLa S3 cells at nanomolar concentrations (IC50, 30-50 nM), was hardly metabolized to (E)-2'-deoxy-2'-(fluoromethylene)uridine (FMdU) which had no antiproliferative activity below 100 microM because of resistance to human cytidine deaminase. MDL 101,731 showed low activity against murine lymphocytic leukemia P388R cells (Ara-C-resistant cells) which contained lower deoxycytidine kinase activity than parental P388 cells. In addition, the antiproliferative activity of MDL 101,731 against HeLa S3 cells was reversed by deoxycytidine. Studies of the intracellular metabolism of 3H-MDL 101,731 demonstrated that it was rapidly metabolized to the diphosphate and the triphosphate forms without the other metabolites in HeLa S3 cells. A 3-h treatment with 0.1-10 microM MDL 101,731 decreased intracellular dNTP pools. The recovery of dNTP pools decreased by treatment with 2 microM MDL 101,731 was much slower than the recovery following treatment with 10 mM hydroxyurea, a reversible ribonucleotide reductase inhibitor. At a dose of 250 mg/kg, MDL 101,731 continuously inhibited ribonucleotide reductase activity up to 72 h in a HeLa S3 xenograft model. CONCLUSIONS: This study suggests that the prolonged ribonucleotide reductase inhibition by rapidly activated metabolites of MDL 101,731 in part contributes to the potent antitumor activity of this drug against various xenografts.

[A case of arachnoid cyst in the posterior fossa with lower cranial nerve palsy].

We experienced a rare case of arachnoid cyst in the right cerebellomedullary cistern. A 59-year-old female was admitted to our clinic because of lower cranial nerve palsy (deviation of uvula to the left side, swallowing disturbance, curtain sign, hoarseness, atrophy of the right sternocleidomastoid muscle, and deviation of the tongue to the right side). MRI demonstrated a mass lesion compressed towards the medulla oblongata in the right cerebellomedullary cistern. MRI was very helpful as a diagnostic tool, since there is no bone object in the posterior fossa. Although by CT cisternography, the arachnoid cyst was thought to have a communication with the surrounding subarachnoid spaces, the cyst wall was removed because of its compressive symptoms on the lower cranial nerves. After the operation, the cyst shrank, and the clinical symptoms were reduced.

[Lymphocytic adenohypophysitis: MRI findings of a suspected case].

We report a case of a 26-year-old woman who had developed decrease of visual acuity, and restriction of the temporal visual field of the left eye in the 30th week of gestation. A skull roentgenogram showed no abnormality, but a pituitary mass was visualized by plain computed tomographic scan. Magnetic resonance imaging (MRI) demonstrated a symmetric sellar mass which had homogeneous signal intensity in all pulse sequences. T1 relaxation time of the mass was elongated as compared with that of a normal pituitary gland. The height of the mass was 11mm, and optic chiasm appeared compressed by the mass. Her visual disturbance improved before delivery, and the size of the pituitary mass regressed spontaneously. Although no histological examination was carried out, the most likely explanation for this phenomenon is lymphocytic adenohypophysitis. Early surgical intervention is not required for lymphocytic adenohypophysitis, because this disorder may be self-limiting, and may resolve itself. Most of these cases have been reported in women, often coincident with pregnancy. So we consider that MRI is the most useful and safest method for diagnosis and follow-up of this disease.

[Magnetic resonance imaging of hypothalamic hamartoma].

Magnetic resonance (MR) findings of two patients with a hypothalamic hamartoma are discussed. The two girls showed clinical symptoms and endocrinological signs of precocious puberty. MR imaging was of diagnostic value superior to that of CT in the demonstration of the characteristic location of this tumor and relationships to the neighboring structures because of its multi-dimensional utility. Although it has been reported that CT showed this lesion as isodense to the grey matter with and without injection of contrast medium, MR imaging depicted the lesion as a high signal intensity area on T 2-weighted images in both patients. MR imaging is a useful method for the evaluation of the hypothalamic hamartoma.

Biodegradability of pesticides in water by microbes in activated sludge, soil and sediment.

A relatively simple, aerobic and anaerobic biodegradation test method for pesticides is proposed. The method consists of the inoculation of the test substance to a substrate of non-acclimated microbes in activated sludge, field soil and river sediment in a stirred flask. This method was applied to the evaluation for biodegradability of twelve pesticides. The biodegradation rate constants obtained showed a parabolic correlation with the 1-octanol-water partition coefficients of the pesticides and a linear one with their alkaline hydrolysis rate constants. Therefore, the biodegradability of pesticides can be predicted by these two parameters.

A proliferation-associated rat cell surface antigen recognized by a murine monoclonal antibody.

B3 murine IgG1 monoclonal antibody against BC47 rat bladder cancer detected an antigen distributed on the cell surface of neoplastic cells and proliferating normal tissue cells. The percentage of B3 antigen-positive cells in lymphocytes was increased by mitogen stimulation. The molecular weight of the antigen was 130,000 or 140,000 daltons.