Characterization of lipophilicity and antiproliferative activity of E-2-arylmethylene-1-tetralones and their heteroanalogues.

A molecular library based on E-2-arylmethylene-1-tetralone has been designed and synthesized. A reversed phase high performance liquid chromatographic (RP-HPLC) method has been developed and applied to separate them and to characterize their lipophilicity. The chromatographic method applied here was suitable to separate the structural (ortho and para) isomers of compounds and was sensitive enough to differentiate their lipophilicities. The measured (k') and computer calculated (CLOGP) lipophilicity values has been compared. Good linear correlation has been found in the case of these structurally related molecules. In vitro biological assay has been performed with Methylene blue dying to investigate the antiproliferative potency of the compounds synthesized in this work. The measured (k') and calculated (CLOGP) lipophilicities of the compounds were compared with the antiproliferative activities and an optimum value of lipophilicity has been found for these compounds.

Antiproliferative efficacy of the somatostatin analogue TT-232 in human melanoma cells and tumours.

BACKGROUND: TT-232, a somatostatin analogue, induces apoptosis in various tumours. The aim of our study was to characterise its effect on human melanoma cells and tumours. MATERIALS AND METHODS: Proliferation of seven melanoma cell lines was tested in vitro with the methylene blue test. D10 and 205 cells were also implanted into CB17-scid mice which received 30-150-750 micrograms/kg/day of TT-232 or saline. Animals with 205 cells received twice-daily subcutaneous injections whereas animals with D10 cells were treated with osmotic mini-pumps. In addition, TT-232 metabolites were generated with tissue homogenates and tested in vitro. RESULTS: TT-232 strongly inhibited proliferation of all cell lines in vitro and tumour growth in vivo. Two out of 8 animals (30-150 micrograms/kg) in the 205 model and one out of 8(150 micrograms/kg) in the D10 model became completely tumour-free at the 11th and 9th day of treatment, respectively. TT-232 was degraded only by liver homogenate whilst its metabolite had no antiproliferative effect in vitro. CONCLUSIONS: TT-232 is a promising drug candidate for melanoma.

Influence of various administration routes on the antitumor efficacy ofTT-232, a novel somatostatin analog.

TT-232 a novel tumor-selective somatostatin analog with a five residue ring structure (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) was developed by us and published in an earlier work. This synthetic heptapeptide had no effect on growth hormone release, but had a remarkable tyrosine-kinase inhibitory effect and inducted apoptosis. The aim of this study was to compare the therapeutic efficacy of TT-232 used in various long-term administration routes and treatment schedules. The effectiveness of TT-232 was studied on different rodent tumors transplanted to inbred mice from SPF breeding. Intermittent treatment by injections and continuous infusion of TT-232 using a s.c., i.p. or i.v. implanted Alzet type osmotic minipump were compared for therapeutic efficacy. The treatments were started either on the day subsequent to tumor transplantation or after the development of a tumor. On the basis of survival and tumor growth inhibition the infusion of TT-232 for 14 days using an implantable osmotic pump proved to be a much more effective route of treatment in both s.c. and i.v. administration than the intermittent injections applied twice a day for 2 weeks. In the case of S-180 sarcoma the continuous administration of TT-232 for 14 days using s.c. implanted osmotic pump resulted in 60% the i.v. infusion produced 40% long-term (over 80 days) and tumor free survivors. By the continuous administration of TT-232, an 80-100% tumor growth inhibitory effect and a considerable retardation of tumor development could be achieved. Continuous infusion from implanted pumps ensured a constant drug level and resulted in a well-defined, consistent pattern of drug exposure over the full duration of drug administration. In our study the route of infusion has been shown to increase drug efficacy relative to conventional delivery methods.

In vivo antitumor activity of TT-232 a novel somatostatin analog.

The somatostatin analog TT-232 containing a 5 residue ring, was previously shown to inhibit the proliferation of a large number of cancer cell lines in vitro and reduce the size of tumors in animal models in vivo. Its action is accompanied by inhibition of tyrosine kinases and is characterized by the induction of programmed cell death. On the other hand, it was proved to be free of the endocrine effects of the natural compound. The aim of this study was to find the optimal dose and administration route for in vivo tumor therapy in an animal model. We have investigated the dose--and administration route-dependent antitumor activity of TT-232 on S-180 sarcoma tumor transplanted to inbred BDF1 mice from SPF breeding. Long-term administration (i.p., s.c. and i.v. injections) was started either on the day subsequent to tumor transplantation or after the development of tumor. The antineoplastic potential of TT-232 was evaluated on the basis of survival and tumor growth inhibition. In long-term administration (injections twice a day for 2 weeks) a significant, but dose- and administration route-dependent therapeutic efficacy of TT-232 was observed. The optimum dose of TT-232 15 micrograms/kg which resulted in a 30-40% cure rate and 50-70% growth inhibition in S-180 sarcoma tumor. A moderate antitumor effect was achieved by TT-232 when it was administered after the evelopment of tumor. Our study suggests that TT-232 can be a promising antitumor agent.

CT or US-guided fine needle aspiration biopsy in gastric neoplasms.

Gastric carcinoma of the linitis plastica type is occasionally difficult to diagnose endoscopically because of the large inflammatory response and the sparsity of tumor cells. Five patients who presented with signs and symptoms of gastric carcinoma underwent upper gastrointestinal endoscopy to confirm the diagnosis of carcinoma. In each case the gross appearance of the stomach was felt to represent gastric carcinoma but the biopsy and/or brushing specimens were unable to make the diagnosis. Ultrasound or CT in each of these five patients demonstrated thickening of the gastric wall and, in one instance, evidence of extensive metastatic disease. Fine needle aspiration biopsy was performed and a diagnosis of adenocarcinoma was made cytologically. Four were primary gastric adenocarcinoma of the linitis plastica type and one was metastatic adenocarcinoma from the breast. It is suggested that guided aspiration biopsy be performed when the diagnosis of gastric carcinoma cannot be confirmed endoscopically.

The varied appearances of hepatic cavernous hemangiomas with sonography, computed tomography, magnetic resonance imaging and scintigraphy.

The incidental detection of an hepatic cavernous hemangioma may create a problem in differential diagnosis. The authors here review the characteristics of hemangiomas as recorded by various types of imaging.

The accuracy of CT in the staging of carcinoma of the prostate.

Previous studies have reported the accuracy of CT in distinguishing stages of prostatic carcinoma, but they lack uniform surgical proof of histopathologic stage. We evaluated CT scans in 32 patients who underwent radical prostatectomy to assess its role in the preoperative staging of prostatic carcinoma. Two experienced radiologists blindly interpreted CT scans of the pelvis; they looked for evidence of tumor beyond the prostatic capsule and involvement of the seminal vesicles (stage C) or involvement of pelvic lymph nodes (stage D). Sixty-four interpretations in 32 patients yielded a specificity of 75% for predicting stages A or B disease (local disease), a sensitivity of 50% for the prediction of stages C or D, and an overall accuracy of staging of 67%. Interpretation errors were due to an inability to detect lymph node metastases, errors in evaluating the seminal vesicles, and errors in interpreting densities surrounding the prostate gland. Our data suggest that CT should not be used to influence decisions concerning surgical vs nonsurgical treatment in patients with clinically staged local disease and is only useful when unsuspected metastatic nodal disease is detected.

Duodenal neoplasms: role of CT.

In a retrospective study of 14 cases of duodenal neoplasms evaluated by computed tomography (CT), there were four primary adenocarcinomas of the duodenum, one lymphoma, five metastatic carcinomas, two duodenal lipomas, one villous adenoma, and one leiomyoma. The CT findings were diagnostic in patients with duodenal lipomas. In 11 cases, a primary origin of the mass was clearly identifiable in the duodenum. Thickening of the bowel wall, tumor necrosis, ulceration, and intraluminal defects were common. The relationship of the masses to adjacent structures was clearly shown on CT scans. Extraluminal extent of the lesion was noted on CT scans in seven patients; however, at surgery only four of six were found to have extramural disease. The presence of adenopathy, liver metastases, and vascular and mesenteric invasion were also demonstrated on CT scans. Twelve patients underwent upper gastrointestinal tract series. A duodenal abnormality was seen in all 12 patients, but the extramural extent and distant metastatic involvement could not be seen on these examinations. CT scans allowed the accurate staging of eight of ten malignant lesions and thus helped in the management of duodenal tumors.

CT diagnosis of dorsal pancreas agenesis.

We report a case of agenesis of dorsal pancreas diagnosed by CT. This anomaly can easily be confused with pancreas divisum on endoscopic retrograde cholangiopancreatography alone.

Further observations in the ultrasound evaluation of renal allograft rejection.

In order to determine whether sonographic parenchymal changes and volume changes are reliable predictors of acute transplant rejection, 36 recipients of renal allografts were studied. The significance of graft volume changes was evaluated, since most previous studies have not utilized routine immediate postoperative baseline scans for comparison to follow-up scans. All patients had baseline scans within 24 hours of the transplant. All 24 acute rejection patients had biopsy proof of rejection within three days of the follow-up scans. Seven clinically normal and five clinically designated acute tubular necrosis (ATN) patients were studied for comparison. A retrospective blind review utilizing three sonologists and previously described criteria combined with calculated volume changes demonstrated an overall sensitivity of 85 per cent and specificity of 94 per cent for the detection of acute rejection. The kidneys with acute rejection had an average volume increase of 73 per cent vs. 27 per cent for ATN patients and 24 per cent for normal patients, a statistically significant difference.