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Biomedical subjects

M J Abrams

Publications and source records attributed to M J Abrams.

32 records · Page 2Linked to original sources
PubMed1991

Platinum coordination complexes which circumvent cisplatin resistance.

In the search for a platinum complex capable of oral administration, the poor bioavailability of established drugs has been circumvented by the discovery of a novel class of platinum (IV) ammine/amine dicarboxylate dichlorides. These compounds, when administered orally to mice carrying the ADJ/PC6 plasmacytoma, exhibit antitumor selectivities far superior to those of cisplatin or carboplatin (given intraperitoneally). Oral activity comparable to that of intraperitoneal cisplatin and carboplatin has also been demonstrated in a panel of human ovarian tumor xenografts. Platinum (IV) ammine/amine dicarboxylates retain cytotoxicity in cultures of L1210/cisplatin and L1210/tetraplatin acquired resistant cells. This property does not translate into a cisplatin-resistant variant of the ADJ/PC6 tumor, in the example of JM221. This result reflects experience with tetraplatin, a drug currently in phase I study, which is comparably ineffective against an ADJ/PC6/cisplatin variant. It is a moot point whether either L1210 or ADJ/PC6/cisplatin-resistant variants are clinically predictive screening models, since this issue must be determined ultimately by clinical study. We have attempted to resolve this dichotomy through the establishment of human ovarian carcinoma lines, both in vitro and in vivo, where there is evidence that response to platinum coordination complexes in the several models reflects that of the donor patient's tumor to platinum-based clinical therapy. The data herein for platinum (IV) ammine/amine dicarboxylates in these models gives encouragement to the notion that these novel compounds may be of value as oral therapeutic agents, whilst also providing an important lead to the discovery and development of a new generation of platinum drugs possessing broad clinical utility.

Animals↗
PubMed1990

Cytotoxicity, radiosensitization, antitumor activity, and interaction with hyperthermia of a Co(III) mustard complex.

A complex of Co(III) with a nitro group and a bis(2-chloroethyl)amine moiety was prepared in an effort to develop a new anticancer agent with radiosensitizing capabilities, direct antitumor activity, and the ability to interact positively with clinically relevant hyperthermia temperatures. The activity of this drug was compared to a similar Co(III) complex, nitro-bis(2,4-pentanedionato)(pyridine)cobalt(III) [Co(Py)], which bears a pyridine moiety mustard of bis(2-chloroethyl)amine and should have no alkylating abilities. In EMT6 cells nitro-bis(2,4- pentanedionato)(bis(2-chloroethyl)amine)cobalt(III) [Co(BCA)] was significantly more cytotoxic than Co(Py) and both drugs were more toxic toward normally oxygenated than hypoxic cells. Hyperthermia (42 degrees C, 1 h) increased the slope of the concentration-dependent survival curve for Co(BCA) but not for Co(Py) in normally oxygenated EMT6 cells. Co(BCA) was an effective radiosensitizer of hypoxic EMT6 cells in vitro, producing a dose-modifying factor of 2.40. In the human squamous cell line SCC-25 and the nitrogen mustard-resistant subline SCC-25/HN2 Co(BCA) was more cytotoxic than Co(Py), and the lethality of Co(BCA) was only minimally diminished in the SCC-25/HN2 line. In mice bearing the L1210 leukemia i.p., Co(BCA) had a broad range of therapeutically effective dosage and produced a greater than 60-day increase in life span at a dose 20-fold less than was lethally toxic. In addition, in the FSaIIC murine fibrosarcoma, Co(BCA) produced a tumor growth delay of 9.4 days at 75 mg/kg i.p. daily x 5, but Co(Py) produced a delay of only 2.9 days at 50 mg/kg daily x 5 and was lethally toxic above this dose. These results indicate that Co(BCA) has significant antineoplastic effects in vitro and in vivo and interacts positively with both radiation and mild hyperthermia. Its broad therapeutic dose range further suggests potential clinical utility.

Animals↗
PubMed1990

Technetium-99m-human polyclonal IgG radiolabeled via the hydrazino nicotinamide derivative for imaging focal sites of infection in rats.

The biologic behavior of human polyclonal immunoglobulin (IgG) radiolabeled with technetium-99m (99mTc) by a novel method, via a nicotinyl hydrazine derivative, was evaluated in rats. Technetium-99m- and indium-111-IgG were co-administered to normal rats and biodistribution was determined at 2, 6, and 16 hr. The inflammation imaging properties of the two reagents were compared in rats with deep-thigh infection due to Escherichia coli. Blood clearance of both antibody preparations was well described by a bi-exponential function: (99mTc-IgG: t1/2 = 3.82 +/- 0.89 and 57.52 +/- 1.70 hr. 111In-IgG: 3.93 +/- 0.117 and 40.71 +/- 1.26 hr). Biodistributions in the solid organs were similar, however, small but statistically significant differences were detected: 99mTc-IgG greater than 111In-IgG in lung, liver, and spleen; 99mTc-IgG less than 111In-IgG in kidney and skeletal muscle (p less than 0.01). At all three imaging times, target-to-background ratio and percent residual activity for the two compounds were remarkably similar. These studies establish that human polyclonal IgG labeled with 99mTc via a nicotinyl hydrazine modified intermediate is equivalent to 111In-IgG for imaging focal sites of infection in experimental animals.

Animals↗
PubMed1989

Effect of heat on the cytotoxicity and interaction with DNA of a series of platinum complexes.

The effect of elevated temperature on the cytotoxicity and interaction with DNA of a series of platinum(II) complexes was examined. CDDP showed greater enhancement in cell killing with heat than the other platinum(II) complexes. There were approximately 2 decades enhancement in cell killing by 10 microM CDDP at 42 degrees C compared to 37 degrees C. The other potential cross-linking agents also showed increasing cytotoxicity with increasing temperature. K2PtCl4 (500 microM) killed about 15 times more cells at 43 degrees C than at 37 degrees C and KPt(NH3)Cl3 (500 microM) killed about 18 times more cells at 43 degrees C than at 37 degrees C. The cytotoxicity of the triammine and tetraammine complexes was less influenced by temperature. There was no significant difference in the cytotoxicity of [Pt(NH3)3Cl]Cl at any of the temperatures examined. The cytotoxicity of [Pt(NH3)4]Cl2 (500 microM) was increased about 7-fold at 43 degrees C compared to 37 degrees C, but the total cell killing by this complex at 43 degrees C was less than 1 log. Carboplatin (250 microM) was about 5 times more toxic at 42 degrees C and killed about 2.5 decades more cells at 43 degrees C than at 37 degrees C. Although there was little enhancement in the cytotoxicity of trans-Pt(NH3)2Cl2 at 42 degrees C compared to 37 degrees C trans-Pt(NH3)2Cl2 (500 microM) was about 7 times more cytotoxic than at 37 degrees C. The interaction of the various drug/temperature treatments with supercoiled pBR322 plasmid DNA was examined to assess the effect of heat on the reaction of these agents with DNA. At 42 degrees C, CDDP was able to gradually alter the gel electrophoretic mobility of the plasmid DNA to near that of the linear form. This change also occurred at 37 degrees C but at a much slower rate. Carboplatin effected similar changes in the superhelical pBR322 DNA, and the effect of temperature appeared to increase the rate of the reaction. Trans-Pt(NH3)2Cl2 also interacted with the supercoiled DNA, but at a slower rate than CDDP even under hyperthermic conditions. These results indicate that neutral platinum complexes capable of cross-linking DNA interact positively with temperature elevation to increase cytotoxicity, and, that of the platinum complexes that meet these criteria, the effect of hyperthermia is greatest with CDDP.

Animals↗
PubMed1989

Potentiation of radiation-induced cell kill by synthetic metalloporphyrins.

The effects of the combination of several meso-substituted, water soluble metalloporphyrins with ionizing radiation on hypoxic and oxic monolayers of Chinese hamster fibroblast (V79N) cells were studied. The metalloporphyrins tested included a series of cationic metalloporphyrins complexed with Co(III), Zn(II), Fe(III), Cu(II), Pd(II) or Mn(III) and a series of anionic porphyrins chelated with Co(III), Fe(III), Cu(II), Rh(III), Mn(III) or Sn(IV). Both cationic and anionic free porphyrins were also tested. Cationic ligands were tetrakis(4N-methylpyridyl)porphine [TMPyP], tetrakis(4N-trimethylamino phenyl)porphine [TMAP], tetrakis(4N-butylpyridyl)porphine [TBPyP] and tetrakis(3N-methylpyridyl)porphine [3TMPyP]. Anionic ligands tested were tetrakis(4-sulfonato phenyl)porphine [TPPS], tetrakis(biphenyl)porphine sulfonate [TBPS] and tetrakis(4-carboxyphenyl)porphine [TCPP]. SER calculated from survival curves and SFR from one radiation dose were used to assess the relative effectiveness of this class as non-cytotoxic hypoxic and oxic cell-kill potentiators. Comparisons were made at 100 microM, which was essentially non-toxic (greater than 70% survival) for all porphyrins tested except for Co[TMPyP] (approximately 50% survival after 1 hour at 37 degrees C under oxic conditions). The greatest effects on radiation-induced cell kill were achieved with Co[TPPS] and Co[TMPyP] with SER values of 2.3 and 2.4 respectively. Porphyrin analogs with no coordinated metal were found to be less active than the same compound with metal. The overall charge on the molecule did not systematically relate to the biological activity of the compounds tested.

Animals↗
PubMed1987

Some complexes of cobalt(III) and iron(III) are radiosensitizers of hypoxic EMT6 cells.

The radiosensitizing potential in hypoxic EMT6 cells of several complexes of Co(III) and Fe(III) has been examined. The cytotoxicity of each of the agents toward oxygenated and hypoxic EMT6 cells was tested over the concentration range of 1 to 500 micron for 1-h drug exposure. There was no statistically significant difference between the cytotoxicity of these complexes toward oxygenated and hypoxic cells. Based on these findings, 100 micron was selected as the drug concentration for the initial assessment of radiosensitizing potential. The radiation survival of EMT6 cells in the presence of 100 microM drug for a series of Co(III) complexes in which the number of nitro ligands was varied showed that the hexanitro and the triamine-trinitro complexes are very effective radiosensitizers. The trans-tetrammine dinitro complex was a more effective radiosensitizer than the corresponding cis-dinitro complex. The diethylenetriamine and 1,10-phenanthroline complexes were very effective radiosensitizers, producing dose-modifying factors of 2.4. The trans-tetrammine dichloro complex was moderately effective, giving a dose-modifying factor of 1.9. On the other hand, the hexammine and triammine tricyano complexes and the trans-dinitro complex with negatively charged acetylacetonate ligands were ineffective as radiosensitizers in this system. Finally, three complexes with cyclopentadienyl ligands were examined. The ferricenium salt itself was a moderately effective radiosensitizer, giving a dose-modifying factor of 2.0. However, both the dimethylferricenium salt and the analogous cobalt complex were ineffective. The FSaIIC fibrosarcoma was used to study radiosensitizing potential in vivo. The trans-tetramminedinitro complex was administered at doses of 100, 200, or 300 mg/kg as a single ip injection 1 h prior to irradiation or as three daily ip injections. There was increasing dose modification with increasing drug dosage. With a fractionated radiation protocol in which five daily fractions of 2, 3, or 4 Gy were administered to the tumor-bearing limb with ip drug injections of 100 or 200 mg/kg given 1 h prior to irradiation, a dose-modifying effect of 1.6 was observed with 5 X 200 mg/kg of the drug.

Animals↗
PubMed1986

Intracellular distribution of a platinum-rhodamine 123 complex in cis-platinum sensitive and resistant human squamous carcinoma cell lines.

The platinum(II) tetrachlorodianion and two molecules of rhodamine-123 associate to form a neutral tight ion pair. To examine the intracellular fate of this ionic complex, the levels of uptake after a 1-hr exposure to a 100 microM concentration of each component of the complex, the complex itself and cis-diamminedichloroplatinum(II) (CDDP) were measured in SCC-25 cells. The uptake of Pt(Rh-123)2 was measured by two independent methods: fluorescence and 195mPt gamma-counting. There was excellent agreement between these two methods as to the amount of Pt(Rh-123)2 which was taken up by the cells, indicating that the Pt(Rh-123)2 is probably entering cell intact. Association with Rh-123 increased the amount of platinum which entered the cells by about 70-fold compared to CDDP and increased by about 700-fold the amount of platinum which entered the cells compared to K2PtCl4. The subcellular distributions of Pt(Rh-123)2, Rh-123, CDDP and K2PtCl4 were also examined. When measured by fluorescence or 195mPt gamma-counting, 40-54% of the Pt(Rh-123)2 was in the nuclei of the SCC-25 or SCC-25/CP cells and 27-35% was in the cytosol of the cells. There was excellent agreement between the findings of fluorescence and 195mPt gamma-counting regarding the amount of Pt(Rh-123)2 in each of the subcellular fractions immediately after incubation with the drug and over the time course of observation after drug removal, indicating that the Pt(Rh-123)2 is probably remaining largely intact intracellularly. On a per mg protein basis, there was about a 55-fold greater amount of platinum in the nuclei of the SCC-25 cells exposed to Pt(Rh-123)2 compared to cells exposed to CDDP. In the SCC-25/CP cells, there was about 258-fold greater platinum in the nuclei of cells exposed to Pt(Rh-123)2 than those exposed to CDDP because CDDP was taken up to a much lesser extent by the SCC-25/CP cells. Association of Rh-123 with potassium tetrachlorodianion forms a tight ion pair, which enters cells in relatively high amounts and is selectively concentrated in the nuclei of the cells.

Antineoplastic Agents↗
PubMed1984

Biological studies of a new class of technetium complexes: the hexakis(alkylisonitrile)technetium(I) cations.

This study describes the preparation and synthesis of a new class of cationic technetium compounds, the hexakis(alkylisonitrile)technetium(+ 1) complexes, at both carrier added and no carrier added concentrations in aqueous media from pertechnetate. Biological distribution and imaging data in animals indicate that certain members of this class may be effective for cardiac imaging in man. The usefulness of these lipophilic water-soluble species for labeling mammalian cells is also reported.

Animals↗
PubMed1984

A new Tc-99m-labeled myocardial imaging agent, hexakis(t-butylisonitrile)-technetium(I) [Tc-99m TBI]: initial experience in the human.

The cationic complex Tc-99m hexakis(t-butylisonitrile)technetium(I) (TBI) has been shown to concentrate in the myocardial tissue of several animal species. In the present preliminary study, the biodistribution of this material was examined in four normal subjects and in two patients with coronary artery disease. In three normal humans injected at rest, planar, tomographic, and gated myocardial images of high technical quality were obtained between 1 and 4 hr after injection. In one subject studied both at rest and during maximal exercise, the lung and heart activities were similar, whereas the liver-to-heart activity ratio was 3:1 at 60 min at rest compared with 1.8:1 with maximal exercise. In two patients with coronary artery disease, transient ischemia appeared as a perfusion defect up to 4 hr after injection at maximal exercise, and the image appeared normal when Tc-99m TBI was administered at rest. The images of areas of infarction appeared abnormal after injection at rest and after injection during exercise. Technetium-99m TBI is a promising myocardial imaging agent that may permit high-quality planar, gated, and tomographic imaging of myocardial ischemia and infarction.

Coronary Disease↗
PubMedDate not supplied

Preparation of hydrazino-modified proteins and their use for the synthesis of 99mTc-protein conjugates.

The syntheses and protein linking properties of succinimidyl 4-hydrazinobenzoate hydrochloride (SHBH) and succinimidyl 6-hydrazinonicotinate hydrochloride (SHNH), two new heterobifunctional linkers which lead to hydrazino-modified proteins, are described. SHBH-modified proteins are unstable due to the presence of the phenylhydrazine moiety. This problem was overcome by synthesizing the hydrazinopyridine analogue SHNH, and the conjugates derived from this linker are stable. Tc(V) oxo precursors readily add to hydrazinopyridine-modified proteins to yield the desired 99mTc-radiolabeled protein. 99mTc-hydrazinopyridine-polyclonal IgG conjugates are useful agents for the imaging of focal sites of infection.

Cross-Linking Reagents↗
PubMedDate not supplied

[99mTc]tricine: a useful precursor complex for the radiolabeling of hydrazinonicotinate protein conjugates.

The stannous reduction of [99mTc]pertechnetate in the presence of tricine results in the formation of the new labeling precursor complex [[99m-Tc]tricine. This complex has improved efficacy for the 99mTc labeling of hydrazinonicotinate-modified IgG compared to [99mTc]glucoheptonate. FAB mass spectral analysis of the product formed by the reaction of [TcOCl4](-1) with tricine indicates the formation of [TcO(tricine x 2H)2](-1).

Cross-Linking Reagents↗
PubMedDate not supplied

A comparison of cleavable and noncleavable hydrazinopyridine linkers for the 99mTc labeling of Fab' monoclonal antibody fragments.

The design and synthesis of hydrazinopyridine bifunctional chelating agents (BCA's) featuring amide, ester, and disulfide groups are described. The BCA's site-specifically react with the free thiol groups of the tumor-specific monoclonal antibody fragment C46.3 using a one-pot in situ reduction and conjugation procedure from the F(ab')2 to give Fab'-linker conjugates. Molar substitution ratios (MSR's) of the hydrazinopyridine conjugates were comparable to the theoretical (maximum) number of thiols per fragment determined by free hydrazine and residual thiol assays. The series of C46.3 Fab'-linker conjugates were 99mTc-labeled in greater than 95% radiochemical purity by incubation with 99mTc-tricine for 1 h at room temperature. In order to evaluate the conjugates for radiopharmaceutical applications, the tumor localization and biodistribution properties of the radiolabeled Fab'-linker conjugates, compared to the direct labeled fragment, were tested in nude mice bearing LS174T xenografts. Depending upon the structure of the linker connecting the radiolabeled hydrazinopyridine group to the antibody fragment, we observed a variation in kidney uptake and whole-body clearance. Diester- and monoester-linked conjugates exhibited lower kidney uptake and faster whole-body clearance than the corresponding linker containing amide groups. This result may be interpreted as evidence for rapid metabolism of ester compared to amide groups in the kidney following uptake. At 24-h postinjection, the monoester-linked conjugate 99mTc-C46.3 Fab'-BA displayed the highest tumor: blood ratio (16.2) compared to the directly labeled conjugate (6.6) and is therefore a potential clinical candidate for imaging breast and ovarian cancer.

Animals↗
PubMedDate not supplied

RP463: a stabilized technetium-99m complex of a hydrazino nicotinamide derivatized chemotactic peptide for infection imaging.

A HYNIC-conjugated chemotactic peptide (fMLFK-HYNIC) was labeled with (99m)Tc using tricine and TPPTS as coligands. The combination of fMLFK-HYNIC, tricine, and TPPTS with (99m)Tc produced a ternary ligand complex [(99m)Tc(fMLFK-HYNIC)(tricine)(TPPTS)] (RP463). RP463 was synthesized either in two steps, in which the binary ligand complex [(99m)Tc(fMLFK-HYNIC)(tricine)(2)] (RP469) was formed first and then reacted with TPPTS, or in one step by direct reduction of [(99m)Tc]pertechnetate with stannous chloride in the presence of fMLFK-HYNIC, tricine, and TPPTS. The radiolabeling yield for RP463 was usually >/=90% using 10 microg of fMLFK-HYNIC and 100 mCi of [(99m)Tc]pertechnetate. Unlike RP469, which decomposed rapidly in the absence of excess tricine coligand, RP463 was stable in solution for at least 6 h. [(99)Tc]RP463 was prepared and characterized by HPLC and electrospray mass spectrometry. In an in vitro assay, [(99)Tc]RP463 showed an IC(50) of 2 nM against binding of [(3)H]fMLF to receptors on PMNs. [(99)Tc]RP463 also induces effectively the superoxide release of polymorphonuclear leukocytes (PMNs) with an EC(50) value of 0.2 +/- 0.2 nM. The localization of RP463 in the infection foci was assessed in a rabbit infection model. RP463 was cleared from the blood faster than RP469 and was excreted mainly through the renal system. As a result of rapid blood clearance and increased uptake, the target-to-background ratios continuously increased from 1.5 +/- 0.2 at 15 min postinjection to 7.5 +/- 0.4 at 4 h postinjection. Visualization of the infected area could be as early as 2 h. A transient decrease in white blood cell count of 35% was observed during the first 30 min after injection of the HPLC-purified RP463 in the infected rabbit. This suggests that future research in this area should focus on developing highly potent antagonists for chemotactic peptide receptor or other receptors on PMNs and monocytes.

Abscess↗