Antisense anti IGF-I cellular therapy of malignant tumours: immune response in cancer patients.

The treatment of cancer by antisense anti-IGF-I cellular therapy inducing immune response has evoked interest among many promising strategies. Here, we reported some results obtained from patients with cancer, mainly glioblastoma treated by this strategy, which was also extended to patients with colon carcinoma, ovary cystadenocarcinoma and prostate adenocarcinoma. It was shown that, in the phase I of clinical trial, patients vaccinated with their own tumour cells treated by antisense IGF-I presented a slight increase of temperature. Their peripheral blood lymphocytes showed a shift in the percentage of CD8 effector cells as judged by expression of cell surface markers CD8+ CD28+. Particularly, in two treated patients with glioblastoma, the survival time was 19 and 24 months respectively in comparison to the range of 12 to 15 months observed in the case of classical treatment such as surgery, radiation or chemotherapy. These results, although preliminary, gave indication that the reported strategy could deserve consideration owing to its safety. Furthermore, the increase in the percentage of peripheral blood monomorphonucleated cells (PBMNCs) with effector phenotype, i.e., CD8+ CD28+ in vaccinated patients might explain their prolonged survival time.

IGF-I triple helix gene therapy of rat and human gliomas.

PURPOSE: IGF-I anti-gene technology was applied in treatment of rat and human gliomas using IGF-I triple helix approach. MATERIAL AND METHODS: CNS-1 rat glioma cell and primary human glioblastoma cell lines established from surgically removed glioblastomas multiforme were transfected in vitro with IGF-I antisense (pMT-Anti-IGF-I) or IGF-I triple helix (pMT-AG-TH) expression vectors. The transfected cells were examined for immunogenicity (immunocytochemistry and flow cytometry analysis) and apoptosis phenomena (electron microscopy). 3 x 10(6) transfected cells were inoculated subcutaneously either into transgenic Lewis rats or in patients with glioblastoma. The peripheral blood lymphocytes (PBL) derived from "vaccinated" patients were immunophenotyped for the set of CD antigens (CD4, CD8 etc). RESULTS: Using immunocytochemistry and Northern blot techniques, the transfected "antisense" and "triple-helix" cells showed total inhibition of IGF. Transfected cultures were positively stained either for both MHC-I and B7 antigens--60% of cloned lines, or for MHC-I only--40% of cloned lines. Moreover "triple helix" cells as compared to "antisense" cells showed slightly higher expression of MHC-I or B7. Transfected cells also showed the feature of apoptosis in 60%-70% of cells. In in vivo experiments with rats bearing tumors, the injection of "triple helix" cells expressing both MHC-I and B7 interrupted tumor growth in 80% of cases. In contrast, transfected cells expressing only MHC-I stopped development in 30% of tumors. In five patients with surgically resected glioblastoma who were inoculated with "triple helix" cells, PBL showed an increased percentage of CD4 + CD25+ and CD8 + CD11b-cells, following two vaccinations. CONCLUSIONS: The anti-tumor effectiveness of IGF-I anti-gene technology may be related to both MHC-I and B7 expression in cells used for therapy. The IGF-I antigene therapy of human glioblastoma multiforme increases immune response of treated patients.

Fixation of the cervical spine using a titanium plate.

Surgery of the cervical spine has been developing since the early twentieth century, but significant progress began with the appearance of the anterior approach, thanks to Bailley, Bedgley and Cloward, who developed a special set of instruments to facilitate operations using the anterior approach. In 1967 Haftek became the first surgeon to perform this operation in Poland; since that time the anterior approach has come to be in more and more general use. The first goal of the operation is to remove fragments of bone and intervertebral discs compressing the spinal cord; the second goal is to achieve good fixation of the operated segment of the cervical spine. In the earlier period external immobilization was applied, using campolite collars, Florida collars, Schanz collars, or HALO stabilizers. Currently immobilizing is done with titanium plates, which are well suited to the purpose of internal fixation of the spine.

Surgical treatment of pathologiesof the craniocervical functions.

Spinal fractures at the craniocervical function require surgical treatment. Surgical can be preceded by direct traction of the cranium in order to set the fragments prior to fixation. This paper presents various methods of fixation from the posterior titanium loops.

Fixation of high thoracic spine fractures. A case report.

Fractures of the thoracic spine are very frequently accompanied by spinal cord compression syndromes, including symptoms that would indicate complete severance of the spinal cord. The indicates a very small reverse of space, especially in the upper and middle segments of the thoracic spine. Even a few millimeters of dislocation among the fragments of broken vertebrae can disrupt the proper anatomical relations and produce neurological deficits. Early intervention - in the form of complete immobilization of the damaged spinal segment, the administration of Solu-Medrol in a dosage consistent with the NASCIS II recommendations, and early surgical treatment with full decompression of the nerve elements - can lead to improvement. Despite the natural splinting provided by the ribs and the sternum, the thoracic spine requires good fixation after the decompression operation, followed in short order by intensive rehabilitation.

[Advances in diagnostic procedures and treatment of spinal neoplasms]. / Postepy w diagnostyce i leczeniu nowotworów kregoslupa.

In the years 1958-1995 in the Department of Neurosurgery in Bydgoszcz we treated operatively 160 patients (100 men and 60 women aged 5-81 yrs) with spinal tumours causing spinal cord compression. Our material was useful in estimating the evolution in diagnostic procedures, treatment and limit of contraindications to surgery. We utilized previously analyzed patients' data from the years 1958-1987 (100 patients) and compared this with results from the years 1988-1995 (60 patients). In the years 1988-1995 we operated on twice as many patients per year than in the period 1958-1987 owing to better diagnostic and operative procedures and decrease of contraindications to treatment. In about 60 percent of patients the tumours were totally and subtotally removed. In recent period we performed 10 initial procedures of transpedicular stabilization. In most cases the extensiveness of tumours did not reach the level of three spinal segments. We confirmed good early results of treatment, particularly in cases with total resection of tumours, in about half the patients with spinal neoplasm, although the most common histological diagnoses were carcinoma (89 cases). In thirty percent of cases with carcinoma only pain was diminished.

The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic.

Butorphanol, a new, totally synthetic morphinan, which is chemically related to naloxone, has been demonstrated to have both analgesic and narcotic antagonist properties. In rodent antiwrithing analgesic tests, butorphanol was 4 to 30 times more potent than morphine and dl-pentazocine, respectively. As an antagonist, butorphanol was about equivalent to nalorphine and 30 times more potent than dl-pentazocine. On the basis of the naloxone-induced mouse jumping test and the lack of substitution in withdrawn morphine-dependent mice, it is estimated that the potential for physical dependence of butorphanol will be less than that of dl-pentazocine but greater than that of nalorphine and dl-cyclazocine. Animal data also show that agonistic actions of butorphanol, such as respiratory depression and miosis, reach ceiling effects which are lower than those seen with morphine with an increase in dosage. Thus, butorphanol differed from morphine which exhibited agonist effects in a dose-related manner. Butorphanol showed weak to moderate central depressant properties at doses which were considerably higher (greater than 100 X) than those producing analgesia. Minimal cardiovascular and respiratory effects were seen with butorphanol in conscious dogs.

Antitussive properties of butorphanol.

Butorphanol (levo-N-cyclobutylmethyl-3, 14-dihydroxy morphinan), a potent analgetic agent of the narcotic antagonist type with a low abuse potential in laboratory animals, was evaluated for antitussive activity in unanesthetized guinea-pigs and dogs. Subcutaneously, it was over 100 times more active than codeine, dextromethorphan and dl-pentazocine and about 20 times more active than morphine in the guinea-pig, while in the dog it was 100, 10 and 4 times more active than codeine, dl-pentazocine and morphine, respectively. Orally, butorphanol was 15-20 times more active than either codeine or dextromethrophan in both species. Naloxone reversed the antitussive effects of butorphanol, codeine, morphine and dl-pentazocine while those of dextromethorphan were not antagonized. The antitussive effect of butorphanol and morphine lasted about 4 hr and both compounds were longer acting than codeine. Butorphanol was also shown to be as effective against cough of pathological origin as against experimentally induced cough in the dog.

Pharmacology of a potent, new antithrombotic agent, 6-methyl-1,2,3,5-tetrahydroimidazo[2, 1-b] quinazolin-2-one hydrochloride monohydrate.

The effect of 6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one hydrochloride monohydrate (BL-3459) on platelet function and experimental thrombosis was evaluated in a series of in vitro, ex vivo and in vivo animal experiments. Potent inhibition of platelet aggregation for BL-3459 was demonstrated by both in vitro and ex vivo techniques. In vitro, EC50 levels were less than 1 mug/ml regardless of the aggregating substance used or the species of animal from which platelet-rich plasma was obtained. After oral administration to rats and dogs, BL-3459 was rapidly absorbed and had a long duration of action. Ex vivo ED50 values were in the range of 2 to 3 mg/kg p.o. In addition, BL-3459 (1-10 mg/kg) demonstrated significant oral activity in a variety of in vivo animal models. BL-3459 inhibited elevation in screen filtration pressure induced by hemorrhage in dogs, endotoxemic death in rats, intravascular thrombosis produced by electrical stimulation of the carotid artery of the dog and thrombosis induced by means of a biolaser in the microvasculature of the rabbit ear chamber. In contrast to acetylsalicylic acid, BL-3459 had little effect on bleeding time in guinea pigs. Oral or intraduodenal administration of BL-3459 to dogs lowered aortic blood pressure, stroke volume and peripheral vascular resistance, while elevating cardiac rate and cardiac contractile force. Thus, it had little effect on the estimated cardiac output. These cardiovascular effects were mediated, in large part, through direct-acting mechanisms. BL-3459 exhibited weak antiserotonin activity in isolated smooth muscle preparations. While the precise mechanism of action of BL-3459 has not yet been determined, indications are that the compound may prove useful in the prevention of intravascular thrombosis.

Comparative effects of kanamycin and amikacin on aortic blood pressure, cardiac rate and surface electrocardiogram in the conscious dog.

Intravenous infusion in conscious beagle dogs of either kanamycin or amikacin to doses of 30 mg/kg resulted in little or no detectible dose related effects on mean aortic blood pressure, cardiac rate, the surface electrocardiogram or gross behavior. Increasing doses of kanamycin and amikacin resulted in dose-related increases in the plasma levels of the two antibiotics. These results indicate that in the conscious dog high plasma levels of kanamycin (64 mug/ml) and amikacin (78 mug/ml) were not associated with depression of systemic blood pressure.

A new method for the evaluation of analgesic activity using adjuvant-induced arthritis in the rat.

A bioassay was developed for the assessment of analgesic activity by using pain resulting from a reproducible pathological condition. The vocalization displayed by rats with adjuvant-induced polyarthritis was defined as an expression of pain, and a decrease of this response was established as specifically demonstrating analgesic activity. This method was capable of detecting the analgesic activity of morphine-like and narcotic antagonist-type analgesics, as well as the activity of the antipyretic analgesics. The relative potencies of known analgesic agents determined with this technique closely approximated the potencies of these analgesics in man. The instrumentation for recording and measuring the vocal response of arthritic rats is described.

Potential antifertility agents. 3. Substituted dibenzothiophenecarboxylic acids and derivatives.

PIP: The syntheses of 37 derivatives of 4-methyldibenzothiophene-3carboxylic acid were reported. Compounds were assayed for their estrogenic and antifertility activities in female mice and rats. In general cis isomers were more active than the trans. In certain postcoital dosing regimens, 2 analogs were more active in preventing or terminating pregnancy in rats than would have been predicted on the basis of their estrogenicity. The effectiveness of these 2 compounds in preventing pregnancy was 100 percent when administered on days 1-5 postcoitum in 1 mg. /kg. / day doses to rats. Effectiveness was the same whether administered orally or slbcutaneously.^ieng