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PubMed1994

The 9L rat brain tumor model for pre-clinical investigation of radiation-chemotherapy interactions.

The rat 9L gliosarcoma brain tumor model has been used for more than thirty years to investigate a variety of potential therapeutic agents, combinations, schedules, and approaches that might be applicable to the management of high-grade malignant brain tumors in man. When tumor cells are implanted intracerebrally, a solid tumor grows until its mass results in the death of the animal, typically between 20 and 30 days postinoculation. Radiation therapy (either single or fractionated doses) is effective at prolonging survival in a dose-dependent manner. Numerous cancer chemotherapeutic agents, by a variety of doses, schedules, and routes of delivery, have demonstrated therapeutic efficacy in the 9L model. The combination of radiation and agents such as AZQ, BCNU, bleomycin, and cis-platinum has resulted in prolongation of survival that is significantly better than either agent used alone, without exceeding the tolerance of critical normal tissues. These pre-clinical data suggest that combining standard fractionated radiation therapy with appropriate concomitant cytotoxic chemotherapeutic agents might benefit patients with high-grade brain tumors.

Animals↗
PubMed1985

Generation of suppressor cells in normal rats by treatment with spirogermanium, a novel heterocyclic anticancer drug.

Daily oral administration of spirogermanium to Lewis rats resulted in the generation of radiation-resistant (2000 Rad) suppressor cells which inhibited the proliferative response of normal spleen cells to an optimum concentration of concanavalin A. These suppressor cells became evident after three to six days of spirogermanium administration. After one day's treatment, although no suppressor cells could be detected, the response of these cells to concanavalin A was less than 50% of controls. Experiments designed to characterize the cell type(s) responsible for this suppression resulted in the finding that T cell-'depleted' populations of spleen cells were more suppressive than T cell-'enriched' populations. The induction of suppressor cells by spirogermanium and the previously described activity in the adjuvant arthritic rat model suggest therapeutic potential for autoimmune diseases.

Animals↗
PubMedDate not supplied

Immunomodulatory activity and non-specific suppressor cell generation by spirogermanium in murine and rat models of cell-mediated immunity.

Spirogermanium (SG) is a metal-containing compound reported to have antitumor, antiarthritic, antimalarial and immunoregulatory activity. In this study we have demonstrated that treatment of mice and rats with spirogermanium results in an inhibition of autoimmune disease and cell-mediated immune (CMI) responses. Prophylactic administration of SG inhibited the development of adjuvant-induced arthritis and the DTH response to purified protein derivative (PPD) in Lewis strain rats. SG treatment was also able to alleviate the symptoms of experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats. In two strains of mice, BDF1 and C57B1/6, the DTH response to sheep red blood cells could be suppressed by intraperitoneal (i.p.) administration of SG. The spleens of both mice and rats that have been treated with this drug contain suppressor cells which inhibit the response of normal cells to concanavalin A (Con A) and the mixed lymphocyte reaction. In addition, the generation of cytotoxic T cells (CTL) in the murine MLR is abrogated in the presence of these suppressor cells. The suppressor cells were radiation-resistant (2000 rad), indomethacin-insensitive and were not depleted by treatment with anti-Thy-1.2 antiserum plus complement. These results suggest that SG modulates cell-mediated immune responses in vivo by the induction of non-specific suppressor cells.

Animals↗
PubMed1990

Antiarthritic and suppressor cell inducing activity of azaspiranes: structure-function relationships of a novel class of immunomodulatory agents.

Spirogermanium (1; 8,8-diethyl-N,N-dimethyl-2-aza-8- germaspiro[4.5]decane-2-propanamine dihydrochloride) is a potent cytotoxic agent in vitro which has demonstrated limited activity in experimental animal tumor models. Subsequently, it has been reported that spirogermanium has antiarthritic and suppressor cell-inducing activity. We have synthesized a series of substituted 8-hetero-2-azaspiro[4.5]decane and 9-hetero-3-azaspiro[5.5]undecane analogues of spirogermanium to identify the heteroatom requirements for in vivo antiarthritic and suppressor cell-inducing activity. This structure-activity relationship study has identified that appropriately substituted silicon and carbon analogues of spirogermanium retain both antiarthritic and immunosuppressive activity, with the 8,8-dipropyl (carbon) analogue being among the most active. Following the identification of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride (9) as a more active analogue than spirogermanium, a series of 8,8-dipropyl analogues with various amine substituents were synthesized. A number of these analogues had activity similar to that of 9. A correlation between activity in the adjuvant arthritic rat and the ability to induce suppressor cells (r = 0.894, p less than 0.001) suggests an association between the two pharmacologic effects. While the precise biochemical mechanism(s) for the pharmacological activity is unclear, these data suggest that compounds within this series, e.g., N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride, may provide effective therapy in diseases of autoimmune origin and/or the prevention of rejection in tissue transplantation.

Animals↗
PubMed2003

Concise, asymmetric total synthesis of spirotryprostatin A.

[structure: see text] The structurally intriguing cell-cycle inhibitor spirotryprostatin A has been synthesized utilizing an azomethine ylide dipolar cycloaddition reaction as the key step. This pentacyclic alkaloid contains a prenylated tryptophan-derived oxindole moiety that has been created in a regiocontrolled and stereocontrolled manner in a single step.

Azo Compounds↗
PubMed2005

Benzylic oxidation catalyzed by dirhodium(II,III) caprolactamate.

[reaction: see text] Dirhodium caprolactamate [Rh2(cap)4] is an effective catalyst for benzylic oxidation with tert-butyl hydroperoxide (TBHP) under mild conditions. Sodium bicarbonate is the optimal base additive for substrate conversion. Benzylic carbonyl compounds are readily obtained, and a formal synthesis of palmarumycin CP2 using this methodology is described.

Benzene Derivatives↗
PubMedDate not supplied

Synthesis of AZA analogues of TSAO.

TSAO derivatives which were first synthesized in 1992 have shown strong inhibitory effect and selectivity against HIV-1 (Camarasa, M.J.; Pérez-Pérez, M.J.; San-Félix, A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35, 2721-2727). The structure-activity relationship of these derivatives has shown strong binding between the amino acids constituting the reverse transcriptase and the different pharmacophore (tert-butyldimethylsilyl group, amino and sulfonate groups of the TSAO derivatives) (Camarasa, M.J.; San-Félix, A.; Pérez-Pérez, M.J.; Velázquez, S., Alvarez, R.; Chamorro, C.; Jimeno, M.L.; Pérez, C.; Gago, F.; De Clercq, E.; Balzarini, J. J. Carbohydr. Chem. 2000, 19, 6403-6406). We described the synthesis of an original TSAO analogue where, basically, the O-1'' atom is replaced by a nitrogen atom.

Anti-HIV Agents↗
PubMed1986

Antiarthritic and immunoregulatory activity of spirogermanium.

Spirogermanium is a novel metal containing azaspirane compound with reported antitumor activity. The results of the present investigation demonstrate that spirogermanium also exhibits antiarthritic and immunoregulatory activities after p.o. administration to rats. Spirogermanium decreased hindleg inflammatory lesions of adjuvant arthritic rats when administered p.o. before or after the development of the arthritic lesions. After termination of spirogermanium administration, the adjuvant-injected hindleg lesions remained significantly suppressed for at least 2 weeks postdrug treatment; whereas, the uninjected, immune-mediated hindleg inflammation tended to increase postdrug treatment. In multiparameter ex vivo studies, untreated arthritic rats exhibited enhanced cyanine dye fluorescence in peripheral blood monocytes, enhanced interleukin (IL)-1 production by adherent spleen cells and depressed IL-2 and IL-3 production by splenic lymphocytes. Spirogermanium normalized these changes to various degrees, with the exception of the depressed IL-2 and IL-3 production. Spirogermanium administered to normal nonarthritic rats decreased mitogenic responses of spleen cells to Concanavalin A which was found to be caused, at least in part, by enhanced suppressor cell activity. The antiarthritic and immunoregulatory profile of spirogermanium appeared to be different from the profiles of the antiarthritic agents, auranofin and indomethacin.

Animals↗
PubMedDate not supplied

Phase II study of spirogermanium in advanced ovarian malignancy.

In the present phase II trial 18 heavily pretreated patients with advanced ovarian malignancy were treated with spirogermanium, 11 im and seven iv. Objective responses (partial remission) were obtained in two (11%) of the 18 patients, with a remission duration of 5 and 23 + months, respectively. An additional four (22%) patients had stable disease. Each of these six patients had a better quality of life. There were few side effects. Myelosuppression, nausea, or other gastrointestinal side effects did not occur. The present investigation shows that spirogermanium is useful as a palliative chemotherapeutic agent in patients with advanced ovarian malignancy.

Adenocarcinoma, Mucinous↗
PubMed1989

Phase II study of N-methylformamide, spirogermanium, and 4-demethoxydaunorubicin in the treatment of non-small cell lung cancer (EST 3583): an Eastern Cooperative Oncology Group study.

One hundred forty-four patients with non-small cell lung cancer, the majority (72%) of whom had received previous chemotherapy, were evaluable in this randomized phase II study of N-methylformamide (N-MF), spirogermanium, and 4-demethoxydaunorubicin. There were two partial responses, one each with spirogermanium and 4-demethoxydaunorubicin. There were eight life-threatening complications (mostly hematologic) and two lethal complications (N-MF, hematologic; 4-demethoxydaunorubicin, gastrointestinal). The overall survival ranged from 9 days to 533 days with a median of 17.6 weeks. The following factors were associated with poor survival: Poor initial performance status, prior weight loss, presence of liver or subcutaneous metastases.

Aged↗