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Biomedical subjects

F E Durr

Publications and source records attributed to F E Durr.

At least 37 records · Page 2Linked to original sources
PubMed1986

The mechanism of action of 3,6-bis(2-piperidinoethoxy)acridine trihydrochloride (CL 246,738) in the potentiation of natural killer cells.

An effort has been made to determine the mechanism by which the immunomodulator 3,6-bis(2-piperidinoethoxy)acridine trihydrochloride (CL 246,738) enhances the cytotoxic activity of natural killer (NK) cells. Orally administered CL 246,738 produced augmentation of NK cell activity in mice in a dose-related fashion over a dose range of 10 to 160 mg/kg, with a peak stimulation occurring at 40 mg/kg. The stimulatory effect was short-lived and only persisted for 3 days after a single oral dose of the drug. However, it could be boosted by a subsequent treatment. With anti-asialo GM-1 (anti-ASGM-1) antibody used as an NK cell marker, it was determined that the compound increased the number of ASGM-1-positive cells in mice, as indicated by radioimmunoassay and immunofluorescence staining. NK cells of beige mice were also activated by CL 246,738. Furthermore, the compound at concentrations of 0.02 to 0.2 microgram/ml induced NK cell activity in vitro, with a minimum 3-day incubation being required for optimal activation. This effect was dependent on the presence of macrophages and was inhibited by anti-IFN-alpha + beta but not anti-IFN-beta antibody. Taken together, it is postulated that the compound functions by stimulating macrophages to release IFN-alpha, which subsequently activates NK cells. As an effective stimulator of IFN and NK cells, CL 246,738 may prove clinically useful in the immunotherapy of certain types of malignancy.

Acridines↗
PubMed1986

Modulation of the immune response to tumors by a novel synthetic compound, N-[4-[(4-fluorophenyl)sulfonyl]phenyl] acetamide (CL 259,763).

CL 259,763, N-[4-[(4-fluorophenyl)sulfonyl]phenyl] acetamide, is an orally active compound capable of modifying the reactivity of certain lymphoid cell populations affected by the growth of a tumor. The compound augmented the response of lymphocytes from tumor-primed animals to syngeneic tumor cells, resulting in a marked increase in tumor cell destruction. Likewise, it enhanced macrophage inhibitory effects on the growth of tumor cells in vitro. These "activated" macrophages were detectable in peritoneal exudates of treated mice 4 to 12 days after receiving a single oral dose of CL 259,763, with peak activity being demonstrable by day 7. The compound also restored the alloreactivity of lymphocytes from immunodepressed mice bearing the Lieberman plasma cell tumor, possibly by interfering with suppressor cells. Macrophages and lymphocytes from treated mice released significantly more IL-1 and IL-2-like factors in culture than did the control counterparts. Sera from treated mice also possessed more colony stimulating factor than those from normal mice. Immunoadjuvant effects were evident when the compound was administered with an inactivated L1210 leukemia vaccine and it enhanced the effectiveness of cytotoxic chemotherapy when given to mice challenged with P388 murine leukemia. These immunomodulating effects of CL 259,763 may hopefully be exploited in efforts to augment the immune response of the host to a progressively growing tumor.

Adjuvants, Immunologic↗
PubMed1986

Inhibition of the induction of alloreactivity with mitoxantrone.

A clinically active anticancer agent, mitoxantrone (MX): 1, 4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9, 10-anthracenedione dihydrochloride, was studied for its potential inhibitory effect on alloreactivity induction. Addition of MX to mixed lymphocyte cultures (MLC) not only inhibited the proliferative response of lymphocytes to alloantigens but also prevented the generation of cytolytic T lymphocytes (CTL). MX showed a long-lasting effect in vitro and acted at the inductive rather than the effector phase of the CTL response as indicated by its failure to alter the activity of those CTL already generated in MLC. MX also inhibited CTL induction in mice. However, the precursors of CTL appeared to be spared in these animals as supported by limiting dilution analysis and also because CTL could be reactivated by exposure of splenocytes to the same or different alloantigens in MLC. The present findings demonstrate that MX is a potent immunosuppressive agent and as such might prove to be clinically useful in the treatment of autoimmune diseases or find utility in the organ transplantation field.

Animals↗
PubMed1986

Tissue deposition of bisantrene in B16 melanoma tumor-bearing mice.

Single doses of 14C-labeled bisantrene, a new antitumor agent, were administered intravenously at 10 and 100 mg/kg to mice bearing intraperitoneally implanted B16 melanoma. At 24 hr after dosing, the tumors contained relatively high drug concentrations as compared to most of the other tissues. The concentrations averaged 2.4 and 28.3 micrograms/g tumor and the tumor/blood concentration ratios were 40/1 and 29/1 for the low and high doses, respectively.

Animals↗
PubMed1986

Immunotherapy of a murine lymphoma by adoptive transfer of syngeneic macrophages activated with bisantrene.

Macrophages from mice treated with a novel antineoplastic agent, bisantrene, were shown previously to be highly active in inhibiting the proliferation of tumor cells in culture. These activated cells have now been found to protect mice from dying of progressive tumors when injected into animals. The effect was observed not only in a Winn-type tumor cell neutralization assay but also in a setting of therapeutic intervention. Multiple treatments with bisantrene-activated cells seemed more effective than a single treatment. Macrophages appeared to be the major effectors in this system, since treatment with carrageenan abolished the protective effect. Thus, present findings suggest that in addition to a direct cytotoxic effect of bisantrene, the activation of macrophages may contribute to the overall antitumor activity of the drug.

Animals↗
PubMed1985

Development of mitoxantrone.

Mitoxantrone (Novantrone; dihydroxyanthracenedione) belongs to a new structural class of antineoplastic agents, the anthracenediones. It was the outcome of a program in synthetic chemistry, at the Medical Research Division of the American Cyanamid Company, which started from a molecule with structural features predicted to favor intercalation with double stranded DNA. The initial lead compound had immunomodulatory effects and was subsequently found also to possess significant activity against transplantable murine tumors. A large series of analogues was synthesized and mitoxantrone was selected for clinical trial on the basis of its potency and excellent antitumor activity in mice. It is a cytotoxic agent that will kill both proliferating and non-proliferating cells. A variety of experiments conducted with both intact cells and cell-free systems have revealed mitoxantrone's ability to bind to single stranded and double stranded RNA and DNA. The drug inhibits cellular RNA and DNA synthesis to about the same extent and causes chromosomal aberrations. In vivo experiments using murine models have demonstrated good activity for mitoxantrone against a variety of transplantable tumors including both leukemias and solid types, in many cases giving putative cures. Surprisingly, it is effective when given up to 30 days before tumor implantation. Combination studies with standard anticancer agents gave evidence of therapeutic synergy in a number of cases. Preclinical studies in several animal models indicate that mitoxantrone does not have the cumulative cardiotoxic liability associated with anthracycline antibiotics such as doxorubicin.

Animals↗
PubMed1985

Induction of tumor-inhibitory macrophages with a novel synthetic immunomodulator, 3,6-bis(2-piperidinoethoxy)acridine trihydrochloride (CL 246,738).

3,6-bis(2-piperidinoethoxy)acridine trihydrochloride (CL 246,738) has been investigated for its immunomodulatory effect on murine macrophages. Incubation of macrophages harvested from the peritoneal cavities of normal mice with the compound for 48 to 72 hr rendered these cells inhibitory to the growth of tumor cells in vitro. Activation of tumor-inhibitory macrophages occurred over a range of concentrations (0.025 to 0.1 micrograms/ml) producing no direct inhibitory effects on tumor cells. Treatment of effector cells with carrageenan abrogated the effect, whereas treatment with anti-Thy-1.2 antibody and C did not, suggesting that the primary effectors were macrophages rather than T lymphocytes. These activated macrophages also manifested in vitro tumor cytolysis. In vivo studies indicated that peritoneal macrophages from mice treated with single oral doses of 100 to 400 mg/kg of the compound were also inhibitory to tumor cell growth in vitro. Effector macrophages became demonstrable in mice as early as 1 day after drug administration, reached peak activity at day 12, and disappeared by day 31, indicating a rapid onset but long-persisting effect. The tumor cytostatic activity of these macrophages was augmented by endotoxin at the dose of endotoxin that, in itself, had no effect. The addition of protease inhibitors, N-alpha-p-tosyl-L-lysine chloromethyl ketone and aprotinin, to cultures markedly diminished the cytostatic effect, suggesting that the release of neutral protease(s) could account for the inhibitory effects of the macrophages. On the other hand, hydrogen peroxide and arginase seemed excluded as the mechanism of action because the effect was not sensitive to treatment with catalase and exogenous arginine. The present findings indicate that CL 246,738 is an orally active immunopotentiator capable of inducing tumor-inhibitory macrophages both in vitro and in vivo.

Acridines↗
PubMed1984

Induction of alloreactive immunosuppression by 1,4-bis [( 2-aminoethyl)amino]-5,8-dihydroxy-9,10-anthracenedione dihydrochloride (CL 232,468).

1,4-bis[2-aminoethyl)amino]-5,8-dihydroxy-9,10-anthracenedione (AEAD) has been investigated for its potential immunosuppressive effect on cell-mediated immune responses. Addition of the compound to mixed lymphocyte cultures (MLC) not only significantly inhibited these cells from responding to alloantigens but also prevented the induction of cytolytic T lymphocytes (CTL). A structurally related compound, mitoxantrone, was also found to be active in inhibiting CTL induction. AEAD had to be present during the first 3 days of a 5-day MLC in order to produce a significant effect and it had no effect on those CTL already generated, suggesting that it acted upon induction of CTL rather than the effector phase. Lymphocytes from mice treated with the compound were incapable of responding to alloantigens in vitro and the effect was dose- and time-dependent. Furthermore, lymphocytes from treated mice were found to inhibit CTL generation from normal mouse lymphocytes, indicating that a suppressor cell population might be induced in the spleens of animals treated with the compound. The present findings clearly demonstrate that AEAD is a compound with potent immunosuppressive activity on alloreactive immune responses.

Animals↗
PubMed1984

Activation of tumor-cytostatic macrophages with the antitumor agent 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazole-2-yl)hydrazone] dihydrochloride (bisantrene).

An investigation was carried out to determine the potential for activating tumor-inhibitory macrophages with the cytotoxic antitumor agent, bisantrene. Macrophages prepared from peritoneal exudates of mice treated i.p. with bisantrene were extremely active in inhibiting the growth of tumor cells. The minimal effective in vivo dose of this drug appeared to be 25 mg/kg, with peak activation being achieved at doses of 50 to 100 mg/kg. Effector cells became detectable 2 days after treatment and persisted for at least 4 weeks. Incubation of effector and target cells for 48 hr seemed necessary to achieve the maximum inhibitory effect. Treatment with carrageenan in vitro and in vivo abolished tumor cytostasis, whereas treatment with anti-T-cell antibody plus complement had no effect, suggesting that macrophages rather than T-lymphocytes were responsible for the observed results. Culture supernatants of activated macrophages were found to have antiproliferative effects on tumor cells, indicating that a cytostatic factor(s) was produced by these macrophages. Hydrogen peroxide and neutral proteases apparently did not function as cytostatic mediators since activated macrophages were resistant to treatment with catalase, N-alpha-p-tosyl-L-lysine chloromethyl ketone, and aprotinin. The present findings suggest that, in addition to direct toxicity to tumor cells, bisantrene may act as a macrophage-activating immunopotentiator. This observation may be of potential clinical usefulness in the design of immunochemotherapeutic trials for certain types of cancer.

Animals↗
PubMed1984

Biologic and biochemical effects of mitoxantrone.

Mitoxantrone (1,4-dihydroxy-5,8-bis[(2-[(2-hydroxyethyl)-amino]-ethyl) amino]-9,10-anthracenedione dihydrochloride) is a representative of a new class of chemical compounds with antineoplastic activity. It was one of a number of polycyclic aromatic compounds tested at the American Cyanamid Laboratories and was the most effective and potent derivative synthesized. Mitoxantrone produced significant increases in life span and long-term survivors when tested against P388 and L1210 leukemias, B16 melanoma, and colon tumor 26 transplanted into mice. In comparative animal trials, it proved more effective than most of the other agents tested, including doxorubicin, cyclophosphamide, methotrexate, cytarabine, and 5-fluorouracil. It was also active against intravenously implanted L1210 leukemia, in contrast to doxorubicin, though this is considered to have a similar mode of action. Mitoxantrone also demonstrated moderate activity against sublines of the mouse leukemias, which were resistant to anthracyclines. Significant therapeutic synergism against P388 leukemia was observed when mitoxantrone was administered on the same day as methotrexate and cytarabine or in sequence with cyclophosphamide, cisplatin, or vincristine sulfate. Mitoxantrone is active intraperitoneally, intramuscularly, subcutaneously, and intravenously, but oral activity has not been demonstrated. Although dose schedule did not appear critical, treatment every 4 days X 3 appeared to be the most effective. The mechanism of action of mitoxantrone has not been fully elucidated, but it is known to inhibit DNA and RNA synthesis. In cell culture, mitoxantrone induces nuclear aberrations with chromosomal scattering and morphologic alterations similar to those induced by doxorubicin. Drug-induced cell kill was not phase specific. Experiments with a resistant human colon carcinoma cell line (WiDr) indicated that resistance may be due to alterations of the cell membrane with decreased uptake. Mitoxantrone has markedly less cardiotoxicity than doxorubicin, and this may be linked to the fact that the drug does not induce free radical formation but inhibits lipid peroxidation.

Animals↗
PubMed1983

Molecular and biochemical pharmacology of mitoxantrone.

Evidence has been presented which indicates that Nv: intercalates DNA and additionally causes inter- and intra-strand crosslinking possibly associated with its charged side arms; there is an apparent preference for G-C base pairs; induces single strand and double strand breaks in DNA; strongly inhibits DNA and RNA synthesis; causes nuclear aberrations and chromosomal scattering; induces a block in the G2 phase of the cell cycle with an increase in cellular RNA and polyploidy; is not cell cycle phase-specific with respect to cell kill; does not induce free-radical formation; does not induce lipid peroxidation or superoxide formation; rather it may inhibit ADR-stimulated lipid peroxidation and microsomal superoxide production; does not appear to have a strong potential for cardiotoxicity on the basis of currently postulated mechanisms of action; is capable of inducing cellular resistance in vitro; resistance is associated with an apparent alteration in the cell membrane impairing drug transport into the cell. Although the precise mechanism(s) of tumor cell killing has not been fully defined it is most likely associated with an interaction by Nv with chromosomes resulting in DNA damage, which if not efficiently repaired, will lead to inhibition of nucleic acid synthesis and eventual cell death.

Animals↗
PubMed1983

Ethambutol dose-plasma level correlation studies in guinea pigs.

Plasma ethambutol concentration-time curves, determined in guinea pigs after 50, 100, or 200 mg/kg single oral doses, were compared with those reported for other species. The plasma concentration-time curve associated with antituberculosis activity in mouse, monkey, and humans could not be reproduced in guinea pigs. In guinea pigs, the rate of ethambutol elimination from plasma (40-min half-life) was 4 times faster than that reported for the mouse or for humans (161-min half-life). This finding tends to negate extrapolation of ethambutol dose-plasma concentration data from other species to guinea pig studies intended to predict clinical utility.

Animals↗
PubMed1982

Antitumor agents. 2. Bisguanylhydrazones of anthracene-9,10-dicarboxaldehydes.

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] (bisantrene, VI-1) showed anticancer activity in mice vs. both leukemias and solid tumors. Increases in life span vs. the following neoplasms were: P-388 leukemia, 137%; B-16 melanoma, 122%; Lieberman plasma cell tumor, greater than 85%; colon tumor 26, 150%; Ridgway osteogenic sarcoma, 85%. There were significant numbers of long-term survivors. Both DNA and RNA synthesis were strongly inhibited. The drug was resistant to biodegradation and was bound strongly to tissues; in monkeys the half-life for disappearance from serum was 6 days. Related hydrazones were synthesized, and structure-activity relationships are discussed. Two routes to ring-substituted anthracene-9,10-dicarboxaldehyde intermediates were developed.

Animals↗
PubMed1982

Activity of a novel anthracenyl bishydrazone, 9,10-anthracenedicarboxyaldehyde Bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride, against experimental tumors in mice.

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride (CL 216942; bisantrene hydrochloride; NSC 337766), a member of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental murine tumor systems. The compound produced significant increases in life span (LS) and long-term survivors among mice bearing transplantable leukemias and solid tumors. Optimal treatment regimens resulted in an ILS of greater than 173 and 151% in mice with P388 and L1210 leukemia, respectively, an ILS of greater than 85% in mice with Lieberman plasma cell tumor, and an ILS of greater than 200, 150, and 63%, respectively, in mice with B16 melanoma, colon tumor 26, and Ridgway osteogenic sarcoma. An adriamycin-resistant subline of P388 leukemia showed complete cross-resistance to CL of 216942. The compound was active when administered by the i.p., i.v., and s.c. routes, but p.o. activity was not observed. Significant schedule dependency was not observed when the drug was administered once daily for 9 days, once every 4 days, or as a single dose, but single doses typically produced the best effects. CL 216942 was a potent inhibitor of DNA and RNA synthesis in L5178Y lymphoma cells cultured in vitro, and preliminary studies indicated the drug was a DNA-intercalating agent. The drug was cytotoxic for rapidly proliferating and nonproliferating (G0) human colon carcinoma WiDR cells in vitro.U

Animals↗
PubMed1979

Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones.

The condensation of alkylenediamines with quinizarin or with 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione, followed by oxidation, gave 1,4-bis[aminoalkyl)amino]-9,10-anthracenediones. Some of these compounds and their 2,3-dihydro derivatives were markedly active against both leukemias and solid tumors in mice. Activity was maximal with 5,8-dihydroxylation and 1,4-bis[(2-aminoethyl)amino] substitution, in which the terminal nitrogen atoms were either unsubstituted (compound 50) or carried 2-hydroxyethyl groups (compound 40), indicating the importance of hydrophilicity. Against B-16 melanoma, 50 gave greater than 433% increase in median life span (ILS) with 7/10 80-day survivors. Against P-388 leukemia, 40 gave greater than 500% ILS with 4/5.60-day survivors; its efficacy and therapeutic index equaled or surpassed those of adriamycin, cyclophosphamide, daunorubicin, methotrexate, or 5-fluorouracil. Against L-1210 leukemia, B-16 melanoma, and colon tumor 26, 40 was generally as effective or more effective than adriamycin and is now undergoing preclinical toxicological evaluation.

Animals↗
PubMed1979

Activity of a novel anthracenedione, 1,4-dihydroxy-5,8-bis(((2-[(2-hydroxyethyl)amino]ethyl)amino])-9,10-anthracenedione dihydrochloride, against experimental tumors in mice.

1,4-Dihydroxy-5,8-bis(((2[(2-hydroxyethyl)amino]ethyl)amino))-9,-10-anthracenedione dihydrochloride (CL 232315; NSC 301739D), a representative of a new chemical class of compounds with antineoplastic properties, has been evaluated for antitumor activity in experimental mouse tumor systems. The compound produced significant increases in life span (ILS) and long-term survivors when tested against the P388 and L1210 leukemias as well as the solid neoplasms, B16 melanoma and Colon Tumor 26. The optimal treatment regimens resulted in a 173 to greater than 200% ILS with 20 to 80% 60-day survivors in mice with P388 leukemia, A 205% ILS with 55% 60-day survivors in mice with L1210 leukemia, and an ILS of greater than 300% with 80% 90-day survivors in mice with B16 melanoma. In contrast to Adriamycin, CL 232315 was active against the i.v. implanted L1210 leukemia and demonstrated moderate activity against P388/Adria, a subline of P388 resistant to Adriamycin. The compound was ineffective when tested against the Lewis lung carcinoma and the Ridgway osteogenic sarcoma. CL 232315 was active i.p., s.c., and i.v., but p.o. activity was not demonstrated. Schedule dependency was not observed when the compound was administered once daily for nine days, once every four days, or as a single dose.

Animals↗
PubMed1977

Clinical evaluation of prophylactic intranasal 1-phenyl-3-(4-phenyl-2-thiazolyl) guanidine (CL 88,277) medication against rhinovirus 44 challenge.

The prophylactic intranasal medication with a new antiviral compound, 1-phenyl-3-(4 phenyl-2-thiazolyl) guanidine (CL 88,277) was evaluated in humans against rhinovirus 44 challenge. One ml containing 250 mg of CL 88,277 was administered to 10 seronegative volunteers three times a day plus one dose prior to the rhinovirus challenge (32 TCID 50) and for six consecutive post-challenge days. Ten other subjects received 56% polyethylene glycol (PEG-400), the solvent of CL 88,277 at the same time. Five subjects in each of the CL 88,277-treated and placebo-treated groups developed illness. There were no differences between the two groups in the occurrence of the severe illness and of the moderate and severe illnesses. Each sign and symptom occurred almost equally in the two groups and there was no difference in their scores between the two groups. The challenge virus was isolated from both groups but the total number of the virus isolates was less and the time span of virus excretion was shorter for the drug-treated group. The post-challenge serum antibody titers were markedly lower in the drug-treated group. Prophylactic intranasal CL 88,277 medication did not affect the course of illness induced by rhinovirus 44 challenge. It appears, however, that the virus replication in the nose was reduced and as a result the serum antibody response was diminished. PEG-400 caused a transient irritation of the nasal mucosa in all recipients.

Administration, Intranasal↗