Biomedical subjects

L R Morgan

Publications and source records attributed to L R Morgan.

At least 19 recordsLinked to original sources

PubMed2001

Anticancer properties for 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007)/3,7-diaminophenothiazin-5-ium double salts.

4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) formed stable double salts with phenothiazin-5-ium salts (2a-d), which have improved in vitro anticancer activities, as compared to A-007 alone. The stable salt between methylene blue (2a) and A-007 allowed the latter to diffuse into the dermis layers of skin. It is anticipated that these new salts will allow A-007 to penetrate into the deep lymphatic/vascular channels of the dermis, which contain metastatic cancer cells, and improve in vivo anticancer activities.

Administration, Cutaneous↗

PubMed2001

Acyl derivatives of demethylpenclomedine, an antitumor-active, non-neurotoxic metabolites of penclomedine.

PURPOSE: The purpose of this investigation was to compare the antitumor activities of a series of acyl derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma metabolite of penclomedine (PEN) observed to be an active antitumor agent in vivo and non-neurotoxic in a rat model with that of DM-PEN. METHODS: Acyl derivatives were prepared from DM-PEN and evaluated in vivo against human MX-1 breast tumor xenografts implanted subcutaneously (s.c.) or intracerebrally (i.c.). Several derivatives were also evaluated against other human tumor xenografts and murine P388 leukemia cell lines. RESULTS: Several of the acyl derivatives were found to be superior to DM-PEN against MX-1, human ZR-75-1 breast tumor, human U251 CNS tumor and the P388 leukemia parent cell line and lines resistant to cyclophosphamide and carmustine. 4-Demethyl-4-methoxyacetylpenclomedine showed inferior activity to current clinical brain tumor drugs against a glioma cell line, superior activity to temozolomide and procarbazine against the derived mismatch repair-deficient cell line, and superior activity to cyclophosphamide and carmustine but inferior activity to temozolomide against two ependymoma cell lines, all of which were implanted s.c. CONCLUSION: Proposed mechanisms of activation and action of DM-PEN and the acyl derivatives support the potential clinical superiority of the acyl derivatives.

Animals↗

PubMed1997

Exposure to male siblings facilitates the response to estradiol in sexually naive female prairie voles.

Female prairie voles undergo induced estrus, and require both physical contact with males and exposure to male urine to become reproductively active. This study attempted to determine if physical contact with males enhanced female response to estradiol. Two groups of sexually naive females were tested. One was reared without any exposure to males after weaning, and the other was reared with sibling males to 60 days of age. Sibling males were used because females avoid direct contact with the urine of related males, allowing for the establishment of a group of females that experienced physical contact in the relative absence of exposure to male pheromones associated with urine. Females were then subcutaneously injected with 0.5 microg estradiol benzoate once a day for 7 days. Sexual receptivity was tested with novel adult males 48 h and 168 h after the first injection. There was a significant difference between the treatment groups, with 10% of sexually naive females reared without sibling males displaying lordosis compared to 70% of females raised with sibling males. The results indicate that exposure to sibling males significantly increased a female's behavioral response to estradiol.

Animals↗

PubMed1996

Relative bioavailability of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) in rats and monkeys.

4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) is being evaluated for its anticancer activities in melanoma, breast cancer, Kaposi's sarcoma and lymphoproliferative disorders. A single oral dose of 1 g/kg of A-007 in rats resulted in prolonged and low plasma levels, typically less than 150 ng/ml for several days. Similarly, a single oral dose of 5 g/kg of A-007 in monkeys resulted in prolonged and low plasma levels, typically less than 22 ng/ml for several days. Oral bioavailability data suggests that this is not an efficient mode of drug administration and availability diminishes as one progresses from rodents to primates (relative oral bioavailability 2%); thus suggesting an alternative form of drug delivery is required in higher species. A-007 is not detected in plasma after a 0.25% gel is applied topically to the skin daily for 28 days. Early clinical support the topical use of A-007 to treat cutaneous metastasis for human breast cancer. The present data further support a dermal approach for the use of A-007 to treat metastatic cutaneous cancers.

Administration, Oral↗

PubMed1995

High-performance liquid chromatographic determination of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone in plasma.

An analytical method has been developed for the determination of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (I, trade name A-007) in plasma. Plasma samples are primed with the internal standard, 2,2'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (II), deproteinized with acetonitrile, centrifuged and filtered prior to assay. The components are then separated on a reversed-phase column with retention times of 4.4 and 6.0 min for I and II, respectively. Ultraviolet detection at 365 nm was employed and little interference with the analyte or the internal standard was noted from other plasma components. This method has been applied to the plasma of rats and monkeys doses for pharmacokinetic and toxicity studies.

Animals↗

PubMed1995

Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study.

Thirty-six patients were entered on this study to determine the pharmacology, bioavailability, and toxicity of three different oral formulations of cyclophosphamide (Cytoxan, Endoxan, and an investigational direct compression tablet). Patients were randomized with respect to the order in which they received the different oral cyclophosphamide preparations, and received each one for two weeks followed by a two week washout period. Concurrent chemotherapy was allowed provided it remained constant across all 3 courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and phosphoramide mustard were measured by gas chromatography with electron capture detection. Peak plasma cyclophosphamide concentrations and times to peak plasma cyclophosphamide and phosphoramide mustard preparations were significantly greater for Endoxan than for Cytoxan and the investigational direct compression tablet. Drug area under the concentration-time curve (AUC), bioavailability, and plasma elimination half-life could not be reliably calculated for Endoxan but were similar for Cytoxan and the investigational formulation. Based on AUC comparisons, bioavailability of parent compound (relative to an oral cyclophosphamide solution) was 85% for Cytoxan and 69% for the investigational formulation. This difference was not significant. There were no significant differences between the 3 formulations with respect to any individual type of toxicity, although the investigational formulation tended to be associated with somewhat less overall toxicity (p = 0.08).

Administration, Oral↗

PubMed1986

High-performance liquid chromatographic determination of N-acetylcysteine in human serum following acetaminophen overdosage.

An analytical method has been developed for the determination of N-acetylcysteine in human serum following acetaminophen overdosage in humans. Serum samples were treated with dithiothreitol and the protein-freed product was derivatized with 2,4-dinitrofluorobenzene. N-Acetylhomocysteine thiolactone was used as an internal standard. Following diethyl ether extraction, the components were separated on a reversed-phase column with retention times of 7.4 and 9.9 min for N-acetylcysteine and internal standard, respectively. Ultraviolet detection at 365 nm was employed and little interference was noted from other serum components. The method has been applied to quantitation of N-acetylcysteine given as treatment for acetaminophen intoxication.

Acetaminophen↗

PubMed1985

Pharmacologic assessment of regimen chemosensitivity in the soft-agar assay: effect of oxygen on human tumors.

The influence of oxygen on the growth and the in vitro chemosensitivity of human tumor cells was studied in the soft-agar assay. Tumor cells of pancreatic and ovarian origin prefer a reduced oxygen atmosphere for colony formation, whereas those of pulmonary origin grow better in 20% oxygen. Depending on the physiologic oxygen tension and the histologic origin of a particular cancer type, the in vitro chemosensitivity of many drug obtained with the conventional culture system could be inadequately assessed. The in vitro responses of tumor cells to combinations of drugs were measured by the regimen efficacy index (REI) method. The REI delineates the possible regimen enhancement or regimen default based on the in vitro chemosensitivity of the individual agents tested in the assay. In vitro regimen enhancement was observed only in ascites incubated in a reduced oxygen atmosphere with two-drug combinations. However, regardless of the oxygen gradients used, regimen default was seen in cancer cells of solid tumors treated with all combinations of drugs tested. This study suggests further investigation on the effects of oxygen in the soft-agar assay, and proposes the novel use of the REI method for evaluating the in vitro regimen chemosensitivity of human tumor cells.

Antineoplastic Agents↗

PubMed1985

Cooperative evaluation of human tumor chemosensitivity in the soft-agar assay and its clinical correlations.

In supporting the human-tumor cloning effort of the Southwest Oncology Group, we conducted an independent retrospective study to evaluate the clinical correlations of the soft-agar colony-forming assay developed by Hamburger and Salmon (1977). This study was made with the cooperation of 76 clinicians and 11 hospitals in Greater New Orleans. In a 10-month trial (July 1982 to May 1983), we received 134 human tumors of 26 classifications and achieved 76% success in colony growth from 122 plated samples. Retrospective correlations between the in vitro chemosensitivity of tumor colonies and clinical drug responses were made possible in 31% of the patients. Evaluation of 45 in vitro and in vivo associations indicated a combined sensitivity of 0.65 and a specificity of 0.68 for the assay. Technical refinements and the selectivity of the assay are discussed.

Antineoplastic Agents↗

PubMed1985

Megestrol acetate v tamoxifen in advanced breast cancer in postmenopausal patients.

One hundred six postmenopausal patients with advanced breast cancer received megestrol acetate or tamoxifen as primary therapy. Response to therapy was comparable for the two agents, with no organ site preference observed for either agent. The median duration of remission was also comparable for the two agents. Both treatments were well tolerated, with weight gain being the most common side effect observed. Initial results of another ongoing study suggest that megestrol acetate is as effective as tamoxifen in hormone-sensitive breast cancer in which receptors have been identified.

Adult↗

PubMed1984

Sectional analysis of tumor colony growth in the soft-agar assay: effects of oxygen.

Soft-agar clonogenicity of L1210 mouse leukemia cells and of xenografts of a human melanoma and a carcinoma of the cervix was studied sectionally by the sizes of the colonies grown under hypoxic gradients and aerobic condition. Soft-agar plating efficiency was increased in cultured L1210 cells with decreasing oxygen concentrations. The growth of both cultured L1210 cells and their BDF1 ascites was better in 5% oxygen than in 20% oxygen. Although soft-agar colony development of both melanoma and cervical carcinoma was significantly better in 5% oxygen, the former has a secondary preference for a hypoxic atmosphere and the latter, for an aerobic condition.

Animals↗

PubMed1984

Effects of sodium warfarin and sodium heparin plus anticancer agents on growth of rat C6 glioma cells.

The effects of racemic sodium warfarin (warfarin) and sodium heparin (heparin) on brain tumor cells were assessed in the rat C6 glioma cell line. After anticoagulant treatment lasting up to 5 days, cell growth was not inhibited by warfarin at low doses (10(-4) to 10(-5) M), but both cell growth and cellular adherence to culture plates were inhibited at high doses (10(-3) to 10(-2) M). Sodium heparin, even at high doses, did not affect cell growth or adherence. Warfarin (10(-3) M) significantly decreased and heparin (12.6 U/ml) had no effect on [3H]thymidine and [14C]leucine incorporation after 3- or 24-hour anticoagulant treatment. Colony formation studies examined the effects of 24-hour warfarin (10(-3) M) or heparin (12.6 U/ml) pretreatment plus a 2-hour incubation with one of seven anticancer agents. Supra-additive toxic effects were produced by warfarin plus chlorambucil, heparin plus chlorambucil, heparin plus carmustine, and heparin plus teniposide. At low doses of warfarin (10(-5) M) or heparin (0.126 U/ml), heparin plus carmustine and heparin plus teniposide remained synergistic.

Animals↗

PubMed1983