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Biomedical subjects

M P Hacker

Publications and source records attributed to M P Hacker.

At least 55 records · Page 3Linked to original sources
PubMed1986

Metabolism of tiazofurin by human erythrocytes and mononuclear blood cells in vitro.

In vitro studies of the uptake, metabolism, and release of tiazofurin by human red blood cells reveal extensive phosphorylation with intracellular trapping of drug predominantly as tiazofurin triphosphate. This phenomenon may explain, in part, the plasma pharmacokinetic profile of tiazofurin. Metabolism of tiazofurin to tiazofurin adenine dinucleotide, the presumed oncolytic metabolite, occurs in mononuclear blood cells but not in erythrocytes.

Antineoplastic Agents↗
PubMed1986

Synthesis and antitumor activities of unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones and related systems.

A number of unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have been synthesized and evaluated for their antitumor activity against L1210 in vitro and in vivo. The high activity of several compounds observed in vitro was not paralleled by comparable activity in vivo. The activities of the substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones as inhibitors of cell growth were generally much higher than those of the related 1-[(aminoalkyl)amino]-4-methoxyanthracene-9,10-diones, and this correlated with the relative abilities of compounds of the two types to interact with calf thymus DNA.

Animals↗
PubMed1986

Water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes as potential antitumor agents.

A series of water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results obtained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cis-dichloro-diammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice inoculated with L1210 leukemia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were administered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against L1210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1, 5, and 9 following i.p. inoculation of B16 melanoma to B6D2F1 mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). N-Benzyl-iminodiacetato(1,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containing material. The exact chemical identity of the active component of this mixture is currently under investigation. The results obtained to date, however, suggest that the N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.

Animals↗
PubMed1986

Toxicity and antitumor activity of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) encapsulated in multilamellar vesicles.

The potential of multilamellar vesicles (MLVs) as carriers of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) (CPDP), a lipophilic cisplatin derivative, was assessed. MLVs composed of dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), and cholesterol at different molar ratios were tested. The MLV-CPDP preparation with the highest antitumor activity against L1210 leukemia in vivo was DMPC:DMPG 7:3-CPDP. The encapsulation efficiency of this preparation was 66 +/- 4% (SD); the stability in 0.9% NaCl solution at 4 degrees C was 89% at 14 days and 93% 18 h after incubation in human AB serum at 37 degrees C. The toxicities of DMPC:DMPG 7:3-CPDP and free CPDP (suspended in hydroxypropyl cellulose) administered i.p. were similar (50% lethal dose = 75 versus 91 mg/kg; blood urea nitrogen values 96 h after the administration of the 50% lethal dose = 32.0 versus 34.4 mg/dl). The mean %T/C [(median survival time of treated mice divided by median survival time of control mice) X 100] obtained after a single i.p. injection of the optimal dose of each preparation tested was 215 (range 200 to 232) for DMPC:DMPG 7:3-CPDP, 175 (range 158 to 209) for DMPG-CPDP, 162 (range 136 to 179) for free CPDP, and 178 (range 169 to 189) for cisplatin. Using a multiple i.p. injection schedule (injections on Days 1, 5, and 9), DMPC:DMPG 7:3-CPDP was more active than free CPDP and cisplatin (%T/C: 403, 284, and 253% respectively). DMPC:DMPG 7:3-CPDP is less toxic and more active against L1210 leukemia in vivo than is cisplatin. The encapsulation of CPDP in MLVs composed of DMPC:DMPG 7:3 provides an adequate vehicle for the administration of this lipophilic compound and enhances its antitumor activity against L1210 leukemia.

Animals↗
PubMed1985

Dissociation of antitumor potency from anthracycline cardiotoxicity in a doxorubicin analog.

The search for new congeners of the leading anticancer drug doxorubicin has led to an analog that is approximately 1000 times more potent, noncardiotoxic at therapeutic dose levels, and non-cross-resistant with doxorubicin. The new anthracycline, 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin (MRA-CN), is produced by incorporation of the 3' amino group of doxorubicin in a new cyanomorpholinyl ring. The marked increase in potency was observed against human ovarian and breast carcinomas in vitro; it was not accompanied by an increase in cardiotoxicity in fetal mouse heart cultures. Doxorubicin and MRA-CN both produced typical cardiac ultrastructural and biochemical changes, but at equimolar concentrations. In addition, MRA-CN was not cross-resistant with doxorubicin in a variant of the human sarcoma cell line MES-SA selected for resistance to doxorubicin. Thus antitumor efficacy was dissociated from both cardiotoxicity and cross-resistance by this modification of anthracycline structure.

Animals↗
PubMed1985

Ascorbato(1,2-diaminocyclohexane):platinum(II) complexes, a new series of water-soluble antitumor drugs.

Dichloro-1,2-diaminocyclohexane (DACH):platinum(II), the prototype DACH:platinum complex, had good antitumor activity, was not cross-resistant with cis-dichlorodiammineplatinum(II) (DDP), but was, unfortunately, virtually insoluble in water and was, therefore, not evaluated clinically. This paper summarizes some of the chemical and biological attributes of a series of cis-bisascorbato-DACH:platinum(II) complexes (DAP). Although the primary emphasis has been placed on the DAP complex consisting of the isomeric mixture DACH, a series of complexes using the isomers of either DACH or ascorbic acid have also been synthesized. The synthetic procedure entailed reacting the water-soluble sulfato-DACH:platinum(II) with barium ascorbate, and the water-soluble product DAP was removed from the BaSO4 precipitate by filtration. Based upon elemental analysis, all the complexes had stoichiometric composition of one DACH:one platinum and two ascorbate monoanions. High-pressure liquid chromatography of cis-bisascorbato (mixed-isomer DACH):platinum revealed a series of platinum-containing, ultraviolet-absorbing peaks. All the DAP complexes had significant in vitro cytotoxicity against L1210 leukemia cells (L1210/0) with 50%-inhibitory dose values ranging from 2 to 5 micrograms/ml. None of the complexes was cross-resistant with DDP when tested in vitro against L1210 cells 50-fold resistant to DDP (L1210/DDP). The cis-bisascorbato (mixed-isomer DACH):platinum (DAP-1) was administered i.p. to C57BL X DBA/2 F1 mice inoculated i.p. with 10(6) L1210/0 cells. When administered on Days 1, 5, and 9, the DAP-1 complex consistently produced treated:control values in excess of 200% with several long-term survivors (alive 60 days after tumor inoculation). Further, the DAP-1 complex was totally non-cross-resistant with DDP when tested in vivo against a DDP-resistant L1210 line. Toxicological investigations revealed that DAP-1 was relatively nonnephrotoxic but did cause the expected bone marrow and gastrointestinal toxicity. In summary, the DAP complexes are highly water-soluble, nonnephrotoxic platinum complexes with sufficient antitumor activity to warrant further pharmacological, biochemical, and chemical investigations.

Animals↗
PubMed1984

Specific antibody synthesis in vitro. I. Technical considerations.

Previously described methods for measuring specific antibody production in vitro are complex and frequently require the addition of a non-specific mitogen and 2 or more separate steps including a lymphocyte culture and then an antibody assay. In this report we present further details regarding a 1-step, non-mitogen requiring assay for specific antibody synthesis combining microculture and enzyme-linked immunoassay techniques. Peripheral blood mononuclear cells from recently immunized subjects are cultured in antigen-coated plastic wells and the specific antibody produced and adhered to the solid-phase antigen is measured in an enzyme-linked immunoassay. The production of specific antibody in vitro did not occur in lymphocyte preparations that were frozen, thawed and incubated, nor did it occur in cultures containing puromycin. T cell separation and remixture experiments indicated that T cells provide significant augmentation under the conditions of this assay. It is apparent that the antibody measured was synthesized in vitro and that cell-cell interactions are operant. The assay may prove useful in the assessment of immune competence and in determining in vitro the effect of certain biologic response modifiers on antibody production.

Antibodies, Bacterial↗
PubMed1984

Efficacy and toxicity of 4-(2-sulfonatoethylthio)-cyclophosphamide cyclohexylamine salt (ASTA Z 7557, INN mafosfamide) after intraperitoneal administration to mice.

4-(2-sulfonatoethylthio)-cyclophosphamide cyclohexylamine salt (AZ; ASTA Z 7557) is a cyclophosphamide (CP) analog designed to be without acute bladder toxicity and to undergo spontaneous activation yielding phosphoramide mustard (PM). Studies in murine systems with intraperitoneal (i.p.) administration suggest that AZ may have a therapeutic index favorable to CP without an associated risk of bladder toxicity. Pericapsular hepatic fibrosis after i.p. administration suggests that regional AZ therapy may cause local toxicity. Further study of this compound, especially with intravenous (i.v.) administration, will be of interest.

Animals↗
PubMed1984

Specific antibody synthesis in vitro. II. Age-associated thymosin enhancement of antitetanus antibody synthesis.

A decline in T cell function accounts for many of the observed age-related deficient immune responses. Specific antibody response to many antigens requires T cell cooperation, and deficient antibody response to such antigens has been demonstrated with aging. In an effort to assess the potential reconstitutive capacity of Thymosin Fraction 5, in vitro antitetanus antibody production was measured in tetanus toxoid booster-immunized young and old volunteers. 22 young and 12 old volunteers were immunized with tetanus toxoid and plasma antitetanus antibody and in vitro lymphocyte production of antitetanus antibody was measured. Plasma antitetanus antibody response was significantly greater in the young. In vitro antitetanus antibody synthesis was negligible prior to immunization and peaked in cultures established 1 week after immunization from both young and old. When Thymosin Fraction 5 was added to the cultures, however, there was a dose-related enhancement of antibody synthesis in 7 of 10 from the group of elderly volunteers, but only 3 of 12 from the younger group. Our data indicate that specific antibody response is deficient in the elderly, but can be enhanced in vitro by thymosin. A future clinical trial of thymosin as an adjuvant to active immunization for the elderly is warranted.

Adjuvants, Immunologic↗
PubMed1984

Experimental tumors and aging: local factors that may account for the observed age advantage in the B16 murine melanoma model.

In the B16 murine melanoma model tumor growth has been shown to be slower in animals of advanced age. One feature associated with this slower growth has been prominent fibrosis demonstrated in biopsies of the tumor in older animals. We have performed experiments to examine the fibrotic response in young and old mice. In non-tumor bearing animals the capacity to regain skin strength after surgical laceration and healing by primary intention was greater in old mice. Histologic preparations suggested a more prominent fibrosis at the wound site. The animals who were injected subcutaneously with B16 melanoma and treated with L 3,4-dehydroproline (an inhibitor of collagen synthesis) local tumor growth was significantly enhanced only for the old animals. Although this inhibition of collagen synthesis produced a differential growth enhancement, there remained a significant difference in tumor volume between young and old animals. We conclude that fibrogenesis is an important host defense for containing local tumor growth and that this mechanism is preserved if not enhanced in mice of advanced age. Nevertheless other factors are needed to account completely for the observed age-advantage in the B16 melanoma model.

Aging↗
PubMed1984

B16 murine melanoma and aging: slower growth and longer survival in old mice.

The growth characteristics and colonization potential of a transplantable melanoma administered to young (3 mo) and old (24 mo) C57BL/6 mice were investigated. After sc injection of B16-F10 melanoma cells, tumor growth was slower, and final tumor volume was less in the older mice. Furthermore, after iv injection of B16-F1 melanoma cells, the number of pulmonary colonies was also less, and the survival was greater in the older mice. These findings indicate an age advantage in this experimental tumor model that may be attributed to either physical or immunologic factors.

Aging↗
PubMed1984

Vinblastine pharmacokinetics measured by a sensitive enzyme-linked immunosorbent assay.

Radioimmunoassays have been developed for pharmacokinetic studies of vinblastine. Although highly sensitive, radioimmunoassays are both expensive and potentially biohazardous. This paper describes a new immunoassay procedure, enzyme-linked immunosorbent assay, which uses enzymatic activity rather than radioactivity as an index of drug concentration. Antiserum to vinblastine was attached to the plastic wells of microtiter plates and incubated in the presence of varying amounts of vinblastine which had been conjugated to alkaline phosphatase. After brisk washing of the wells, p-nitrophenylphosphate was added to each well. The amount of enzyme present in the well was quantitated by the production of the chromophore, p-nitrophenol. The concentration of free vinblastine present in a given sample was inversely proportional to the enzymatic activity. The enzyme-linked immunosorbent assay is capable of detecting as little as 5 pg of either vinblastine or vincristine and is not cross-reactive with other commonly used oncolytic agents. A pharmacokinetic study was performed in rats administered vinblastine i.v., and a triphasic elimination curve was obtained. These results indicate that the enzyme-linked immunosorbent assay provides a nonradioactive, inexpensive, and sensitive method to monitor plasma levels of vinblastine. Further, since the antibody is cross-reactive with vincristine, it would appear that similar data could be generated for vincristine.

Alkaline Phosphatase↗
PubMed1983

Fibrogenic structure-activity study of the bleomycin molecule.

In the present study the fibrogenic potential of intact bleomycins as well as their acetyldipeptide and terminal polyamine constituents have been assessed. Administration of Blenoxane, bleomycin A2, or bleomycin B2 to rats produced histopathologic evidence of pulmonary fibrosis when tissues were examined 28 days following a single intratracheal dose. These compounds also produced a readily detectable increase in pulmonary collagen synthesis as evidenced by an approximate twofold increase over control values in the formation of [3H]hydroxyproline in an in vitro lung mince system. Lung collagen synthetic activity remained significantly elevated over control values for up to 2 weeks. However, neither the acetyldipeptides nor the polyamine constituents of bleomycin A2 and B2 produced detectable increases in lung collagen synthesis or in histopathologic evidence of pulmonary injury. Spermine and spermidine, the terminal amine components associated with bleomycin-A6 and with tallysomycin A, tallysomycin B, and bleomycin-A5, respectively, did produce significant pulmonary fibrotic injury in rats following intratracheal administration. Out of an extensive series of polyamines, bleomycin acetyldipeptides and intact bleomycin and tallysomycin analogs, only spermine and spermidine were found to produce hydrogen peroxide and acrolein upon incubation in vitro with amine oxidase, a common pulmonary enzyme. Conclusions regarding the relative toxicity of different bleomycin analogs based solely on the toxicity produced by administration of their terminal amine constituent must therefore be made with caution.

Animals↗
PubMed1983

The effect of L-3, 4-dehydroproline on the antitumor activity and toxicity of bleomycin.

Pulmonary fibrosis is a serious side effect that limits the therapeutic utility of bleomycin (BLM). Recently, it has been demonstrated that L-3, 4-dehydroproline (DHP), a proline analog, significantly reduced the extent of pulmonary fibrosis in rats administered BLM intratracheally. The present studies were performed to determine the effect of DHP on the oncolytic and toxicologic effects of BLM. DHP (25 mg/kg/day) administered sc concomitantly with BLM (4 mg/kg/day) for 9 consecutive days following a sc inoculation of B16 melanoma cells in BDF1 had no effect on tumor growth inhibition by BLM when tumor growth rate was assessed by tumor volume and by tumor weight. To determine the effect of DHP on the toxicity of BLM, DHP (25 mg/kg/day) and BLM (10 mg/kg/day) were administered to Sprague-Dawley rats for 5 consecutive days followed by 2 days of rest and 5 additional days of drug administration. BLM administration produced decreased body weight gain, acute leukocytopenia, delayed elevation in blood nitrogen levels, chronic lung and kidney disease, and alopecia. Animals administered BLM plus DHP had a similar toxicologic profile. One striking difference was that no animal administered BLM plus DHP developed alopecia, whereas five of eight rats administered BLM alone displayed this untoward effect. These results suggest that DHP neither diminishes the oncolytic activity nor exacerbates the nonpulmonary toxicity of BLM, DHP would appear, therefore, to be a potential candidate as an antifibrotic adjunct to BLM therapy.

Animals↗
PubMed1983

Cimetidine and the immune response. I. In vivo augmentation of nonspecific and specific immune response.

Cimetidine is a commonly prescribed histamine antagonist useful in the treatment of peptic ulcer disease. Histamine receptors are found on suppressor T cells and therefore we expected to observe enhanced immune responsiveness in animals treated with this drug. Mice given daily subcutaneous injections of cimetidine (25 or 100 mg/kg) were found to produce approximately twice as much specific antibody in response to tetanus toxoid immunization. Furthermore, mitogen-stimulated splenocytes from cimetidine-treated animals proliferated to a greater extent and produced more immunoglobulin in vitro than controls. These observations offer direct in vivo evidence for immunomodulation by cimetidine.

Animals↗
PubMed1983

Reduction of acute adriamycin toxicity in mice treated with adenosine.

The effects of adenosine on the acute toxicity and oncolytic activity of adriamycin (ADR) were evaluated in mice. When administered as a single i.p. injection of 17.5 mg/kg, adriamycin produced death in all mice within 12 days after treatment, with a mean survival time of 5-9 days. In contrast, the mean survival time of mice administered adenosine subcutaneously (200 mg/kg) in addition to adriamycin was significantly increased compared to adriamycin-treated mice. The protection elicited by adenosine was apparently not a generalized phenomenon of purines, however, since neither hypoxanthine nor inosine were effective protectants. Although a number of adenosine treatment schedules were tested, it was found that adenosine given immediately after adriamycin was as effective as multiple adenosine injections. Administration of adenosine had no apparent effect on adriamycin-mediated changes in ventricular weight, leukocyte count, elevated serum lactic dehydrogenase (LDH) activity or in the histopathologic changes observed in selected tissues. Two grossly observable effects of adenosine administration were lethargy and peripheral hypothermia, which were first noticed approximately 15 min after adenosine administration and which lasted for up to 2 hr. Finally, adenosine had no adverse effect on the antitumor efficacy of adriamycin against L1210 ascites cells inoculated i.p. to BDF1 mice.

Adenosine↗