Efficacy and toxicity of VAC chemotherapy (vincristine, doxorubicin, and cyclophosphamide) in dogs with hemangiosarcoma.

Fifteen dogs with hemangiosarcoma were treated with a combination of vincristine, doxorubicin, and cyclophosphamide after incisional or excisional biopsy. The median survival for all fifteen dogs was 172 days (mean survival = 316 days). The median survival for those dogs with splenic hemangiosarcoma was 145 days (mean survival = 271 days) as compared with previously published median survival times in dogs with splenic hemangiosarcoma treated with surgery alone of 19 to 65 days.

4-Demethoxy-3'-N-trifluoroacetyldoxorubicin. Synthesis and solid tumor activity.

A new route has been developed for the preparation of 3'-N-protected doxorubicin analogues. 4-Demethoxy-3'-N-trifluoroacetyldoxorubicin (5) was synthesized in an approach to an orally active anthracycline analogue. Tested against the B-16 murine solid tumor in mice, this compound increased life span by 133% when it was administered intraperitoneally at 25 mg/kg, and by 52% when it was given orally at 50 mg/kg.

Mono and bis(bioreductive) alkylating agents: synthesis and antitumor activities in a B16 melanoma model.

Several potentially bis(alkylating) bis(quinones) (3-5) and 1,4- and 1,3-bis(alkylating) monoquinones (6-13) belonging to general structure 2,2'-ethylenebis[5-[(leaving group)methyl]-1,4-benzoquinone] (3-5) and 2,5- and 2,6-bis[(leaving group)methyl]-1,4-benzoquinone water-soluble and -insoluble classes were prepared by oxidative demethylation of the corresponding tetramethoxydiphenylethanes (17-19) and dimethoxybenzenes (24, 27, 36-39), respectively. Methods employed for the preparation of tetramethoxydiphenylethane intermediates involved (1) arylmethyl bromide coupling and (2) catalytic hydrogenation of stilbene intermediates derived via Wittig reaction of (arylmethyl)phosphonium salts with aryl aldehydes. However, in biological investigations using a subcutaneous B16 (hypoxic) melanoma tumor in BDF1 hybrid mice with cyclophosphamide as positive control the most interesting series of structurally related analogues were the potentially monoalkylating monoquinones of the 2-[(leaving group)methyl]-1,4-benzoquinone type (i.

Synthesis and P-388 antitumor properties of the four diastereomeric 1-hydroxy-3,4-diaminocyclohexane-Cl2PtII complexes.

Synthesis and antileukemic activity in vivo of the four diastereomeric 1-hydroxy-3,4-diaminocyclohexane-Cl2PtII complexes (Cl2PtII-3a-d) are described. Respective bis(phenylmethyl) (1 alpha,2 alpha,4 beta)-, (1 alpha,2 alpha,4 alpha)-, (1 alpha,2 beta,4 beta)-, and (1 alpha,2 beta,4 alpha)-(4-hydroxy-1,2-cyclohexanediyl)bis(carbamates) (5a, 5b, 7a, 7b) were prepared by hydroboration-oxidation of the bis(carbobenzoxyamino) derivatives (4,5) of cis- and trans-4,5-diaminocyclohexene. The relative stereochemistry of intermediates 5a and 5b was established by correlation with the alcohol obtained by NaBH4 reduction of bis(phenylmethyl) (1 alpha,2 alpha,3 alpha,4 alpha)-(3,4-epoxy-1,2-cyclohexanediyl)bis(carbamate) (8), the all-cis stereochemistry of which was unambiguously determined by X-ray crystallographic analysis.

Stereocontrolled syntheses for the six diastereomeric 1,2-dihydroxy-4,5-diaminocyclohexanes: PtII complexes and P-388 antitumor properties.

Stereocontrolled syntheses for the six diastereomeric 1,2-dihydroxy-4,5-diaminocyclohexanes 3a-f from cyclohexene diamines cis-4 and trans-5 are described. Cbz-protected species cis-9 and trans-11, respectively, served as a source of stable Cbz-protected precursors to these cyclohexanediol diamines (CDD), which were liberated upon catalytic (H2, Pd/C) hydrogenation. Catalytic osmylation of 9 afforded a mixture of diastereomeric diols 13 and 14, which served as precursors to cis-anti-cis CDD 3b and cis-syn-cis CDD 3a, respectively, whereas osmylation of 11 yielded the expected single product 12, the precursor to cis-anti-trans CDD 3d.

N-(2-hydroxyethyl)doxorubicin from hydrolysis of 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin.

The susceptibility of 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin to hydrolysis at pH 7, 4, and 2 has been compared with that of the typically stable morpholine analogue. At pH 7, 74% of the cyanomorpholine was unchanged after 24 h at room temperature, but at pH 2 only 10% remained. Products identified were aglycon (8%) and N-(2-hydroxyethyl)doxorubicin (7%).

N-(cyanomethyl)- and N-(2-methoxy-1-cyanoethyl)anthracyclines and related carboxyl derivatives.

Treatment of doxorubicin with formaldehyde and NaCN afforded the N-(cyanomethyl) derivative as a stable alpha-cyanoamine with but moderate antitumor activity in mice, although it was prototypal to the intensely potent alpha-cyanomorpholine derivative. 2-Methoxyacetaldehyde and NaCN afforded the N-(2-methoxy-1-cyanoethyl) derivative as an open-chain analogue of the cyanomorpholine. This analogue underwent rapid hydrolysis to doxorubicin and appeared to act as a prodrug, giving increased antitumor efficacy although with decreased potency.

Total chemical synthesis and antitumor evaluation of the 9-aza analogue of N-(trifluoroacetyl)-4-demethoxydaunomycin.

The 9-aza analogue of N-(trifluoroacetyl)-4-demethoxydaunomycin has been synthesized from 2,5-dimethoxybenzaldehyde. Pomeranz-Fritsch condensation followed by borohydride reduction and acid-catalyzed cyclization led smoothly to 4-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline. Selective N-acetylation and subsequent Friedel-Crafts acylation with phthalic anhydride produced 2-acetyl-5,12-dihydroxy-1,2-dihydro-2-azanaphthacene-6,11-dione, which was protected as its dimethyl ether and epoxidized to an acylated aza Brigl's anhydride.

New cyanomorpholinyl byproduct of doxorubicin reductive alkylation.

Previously we reported that reductive alkylation of doxorubicin with 2,2'-oxybis[acetaldehyde] and NaBH3CN to form the 4''-morpholinyl derivative also gave the intensely potent 3''-cyano-4''-morpholinyl as a byproduct, by addition of CN- to an iminium intermediate in place of hydride. We now find that sugar 4'-OH is a third nucleophile that can add to the iminium intermediate in this reaction. Bridging of the 4'-OH to the morpholine ring at C.

Chemical carcinogenesis and immunity: immunologic status of rats treated with methylnitrosourea.

During the treatment of outbred Sprague-Dawley rats with methylnitrosourea (MNU) or the noncarcinogenic analog diphenylnitrosamine, antibody levels to teichoic acid as well as several parameters of lymphocyte and macrophage function were assessed in animals not overtly stimulated with antigen. Treatment with MNU did not appear to alter most immunologic parameters studied. Some alterations occurred in natural antibody levels, in spleen weight, and in peripheral blood differentials of rats that had received the highest carcinogen dose (4.

Direct identification of the murine pluripotential stem cell using rabbit anti-mouse brain serum.

Previous studies have shown that antisera prepared in rabbits against mouse brain tissue (RAMBS) contain activity against the murine bone marrow colony-forming unit (CFU-s) or pluripotential hemotopoietic stem cell. In the present study, the F(ab')2 portion of RAMBS was examined for its potential efficacy in the identification of the mouse CFU-s when used in an indirect immunofluorescence-labeling technique. After separation of mouse bone marrow cells by a discontinuous bovine serum albumin density gradient, fluorescent cells were observed only in those bands which, by the splenic colony-forming assay, demonstrated CFU-s.

Effect of a sulfhydryl inhibitor on in vitro bone marrow colonies (CFU-c).

A dose-related increase in the number of in vitro colony-forming units. CFU-c, was observed in mouse bone marrow cell suspensions following the administration of the sulfhydryl inhibitor, sodium iodoacetate. No effect on CFU-s was observed at the dosages and the periods selected for examination.

Effect of iodoacetate on T lymphocytes of young AKR mice.

The influence of sulphydryl inhibitor iodoacetate on properties characteristically associated with T-lymphocytes was examined in young AKR mice. Thymocytes from mice receiving 100 microgram of iodoacetate showed a decrease in cortisone sensitivity, and responded more vigorously to phytohemagglutinin (PHA). Spleen cells from treated mice also exhibited greater reactivity to both PHA and concanavalin A (Con A).

Iodoacetate-induced inhibition and enhancement of spontaneous leukemia in AKR mice.

Either inhibition or enhancement of the spontaneous lymphoma exhibited by AKR mice was observed after treatment with different dosages of the sulfhydryl inhibitor, sodium iodoacetate. Treatment of the mice at 3 or 6 months of age with five ip injections of 0.10 mg of iodoacetate at 5-day intervals significnatly extended the survival of the animals.

Detection of Thiobacillus ferrooxidans in acid mine environments by indirect fluorescent antibody staining.

An indirect fluorescent antibody (FA) staining technique was developed for the rapid detection of Thiobacillus ferrooxidans. The specificity of the FA stain for T. ferrooxidans was demonstrated with both laboratory and environmental samples.

Antigenic cross-reactivity among rodent brain tissues and stem cells.

Previous studies have shown that antisera prepared in rabbits against mouse brain (RAMB) contains activity in vitro against the mouse bone marrow colony-forming unit (CFU) or hematopoietic stem cell. In the present study, in vitro treatment of mouse bone marrow with antisera prepared in rabbits against brain tissue from rats (BARB) or hamsters (RAHB) also reduced the CFU content of the mouse marrow. Prior absorption of the RAMB serum with fetal liver tissues from rats or hamsters as well as mice reduced the anti-CFU activity of the RAMB preparation.

Identification of hamster thymus-derived lymphocytes employing rabbit anti-hamster brain serum.

Rabbit anti-hamster brain sera prepared from the brains of Syrian and Chinese hamsters were evaluated for their potential to identify thymus-derived lymphocytes present in these animals. The unabsorbed antisera were cytotoxic in vitro for both homologous and heterologous thymocytes and splenocytes. Following absorption with hamster liver and erythrocytes, the antisera remained toxic for thymocytes, but were less toxic for splenocytes.

Effect of iodoacetate on the bone marrow immunocompetence of AKR mice.

Studies were conducted to determine whether the sulfhydryl inhibitor, sodium iodoacetate, administered to preleukemic AKR mice and to mature C3H mice altered the immunocompetence of their bone marrow. Parameters investigated included the splenic plaque-forming capacity directed to sheep erythrocytes of bone marrow transferred from iodoacetate-treated aanimals to irradiated syngeneic recipients and the mitogenic responsiveness of bone marrow cells from untreated and iodoacetate-treated preleukemic AKR mice to phytohemagglutinin and concanavalin A. The administration of two 0.

In vivo effects of rabbit anti-mouse brain serum on theta bearing lymphocytes of AKR mice.

The in vivo effect of rabbit anti-AKR mouse brain-associated serum (RAMB) was determined on theta bearing lymphocytes present in the spleens and thymuses of mature C3H mice and AKR mice staged into preleukemic, leukaemic and overtly leukaemic states. Following seven daily injections of RAMB serum, the splenic plaque-forming cell (PFC) response to sheep erythrocytes (SRBC) and the percentage of theta-bearing lymphocytes in the spleen were significantly decreased in the C3H and the preleukaemic AKR mice. Decreases in thymic weight and thymocyte numbers were also apparent.