Biomedical subjects

R T Dorr

Publications and source records attributed to R T Dorr.

154 records · Page 9Linked to original sources

PubMedDate not supplied

Effect of interferon, interleukin-2 and tumor necrosis factor on myocardial cell viability and doxorubicin cardiotoxicity in vitro.

Neonatal rat heart myocytes were cultured in plastic 24-well plates for 6 days over which time ATP and protein levels steadily increased. Synchronous beating rates of 40-50 per min are obtained 3 days after plating 1.14 x 10(6) myocytes/well. The addition of rat interferon (IFN) or recombinant human interleukin (IL-2) or tumor necrosis factor (TNF) at concentrations of 10-1000 U/ml for 24-48 h did not reduce ATP/protein ratios or significantly affect beating rates. A 6-h exposure to doxorubicin concentrations of 0.5 micrograms/ml and 1.0 microgram/ml reduced control ATP/protein ratios of 6.8-7.3 ng/microgram by 78% and 40%, respectively. Importantly, the addition of 100 U/ml of IL-2, TNF or IFN to these doxorubicin concentrations did not alter doxorubicin-induced cardiotoxicity. These results suggest that IL-2, TNF and IFN do not cause direct myocardial cell damage and may be cautiously combined with doxorubicin without enhanced cardiotoxic effects. The reported cardiotoxicity from such cytokines may be principally due to peripheral vascular effects which reflexly stress the heart.

Adenosine Triphosphate↗

PubMedDate not supplied

Approaches to reducing toxicity of parenteral anticancer drug formulations using cyclodextrins.

Mitomycin C (MMC) is a clinically useful anticancer drug which can cause severe dermatological problems upon injection. It can cause delayed erythema and/or ulceration occurring either at or distant from the injection site for weeks or even months after administration. In an attempt to reduce the skin necrosis, complexation of MMC with cyclodextrins was studied in order to help increase patient compliance and acceptance. The complexation of MMC with 2-Hydroxypropylbetacyclodextrin (HPBCD) in the presence and absence of mannitol was studied and it was found that the mannitol present in the commercial formulation caused an increase in the binding of MMC to HPBCD. Isotonicity adjustment of hypotonic MMC formulations by the addition of normal saline did not change the degree of complexation with MMC. The complexed formulations were then tested to determine their antitumor efficacy using the B-16 melanoma cell model. No difference in antitumor activity between the complexed and uncomplexed MMC formulations was observed. Different MMC formulations were tested for their potential to produce skin irritation and/or toxicity using intradermal injections in a BALB/c mouse model in order to find the most suitable formulation. The skin ulceration studies indicated that there were no significant differences between the isotonic MMC solution and isotonic formulations of MMC complexed with HPBCD.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMedDate not supplied

Case report: topical DMSO for mitomycin-C-induced skin ulceration.

Mitomycin-C is a commonly used anticancer drug for patients with advanced anal, breast, colorectal, gastric, lung, or pancreatic cancers. Mitomycin-C can cause severe necrosis and ulceration when extravasated inadvertently into skin and soft tissues following IV drug administration. Local applications of heat, ice, and common antidotes such as glucocorticosteroids and hyaluronidase or sodium thiosulfate have failed to reduce the experimental toxicity of these vesicant reactions in mice. Plastic surgery with split-thickness skin grafting may be required to palliate local pain symptoms and loss of function, although some extravasations heal without any local treatment. This brief communication summarizes two case reports of the treatment of severe mitomycin-C venous extravasations using topical applications of dimethylsulfoxide (DMSO). Although the authors' experience represents the results of DMSO interventions in only two patients, the response to treatment in both patients was so pronounced that others may find this useful in their practice.

Administration, Topical↗

PubMedDate not supplied

Mitomycin C toxicity and pharmacokinetics in mice given sulfur nucleophiles.

The sulfur nucleophiles, sodium thiosulfate (Na2S2O3) and N-acetylcysteine (NAC) given in maximally tolerated doses did not reduce the hematologic toxicity of high dose mitomycin C (MMC) in normal mice. In addition, neither sulfur nucleophile significantly altered the antileukemic activity of MMC. Pharmacokinetic studies of MMC in normal mice, demonstrated rapid plasma elimination (T1/2 beta = 0.53 hrs) and substantial drug distribution to the bone marrow which was enhanced by NAC. These results demonstrate a lack of MMC antidotal activity for Na2S2O3 and NAC.

Acetylcysteine↗

PubMedDate not supplied

Lack of enhanced antitumor efficacy for L-buthionine sulfoximine in combination with carmustine, cyclophosphamide, doxorubicin or melphalan in mice.

A series of studies was performed in tumor bearing mice to evaluate the impact of glutathione (GSH) depletion by L-buthionine sulfoximine (L-BSO). L-BSO doses of 50 or 500 mg/kg were used alone or with one of 4 sulfhydryl-dependent anticancer agents (SHDAA). When L-BSO was administered to tumor-bearing mice, Colon 38 cells were significantly depleted of GSH content, but this did not occur with P388 cells or MOPC-315 cells in vivo. GSH levels in these ascites tumors declined significantly without L-BSO treatment as the tumor rapidly grew in the IP space. SHDAAs, including doxorubicin (DOX), cyclophosphamide (CTX), carmustine (BCNU) and melphalan (L-PAM) were then combined with L-BSO in mice bearing P388, MOPC-315 or colon 38 tumors. There was no consistent enhancement of antitumor efficacy using a treatment interval of 24 hrs (L-BSO given first). In contrast, there was some evidence of significantly enhanced SHDAA toxicity with L-BSO. Further studies should evaluate different dosing intervals to take advantage of the slower rate of GSH replenishment observed in normal tissues compared to solid tumor cells (Colon 38) in vivo. In addition, significant reductions for any SHDAA combined with L-BSO are indicated in any such trial.

Animals↗

PubMedDate not supplied

Methotrexate: bioavailability and pharmacokinetics.

Six adult patients with squamous cell carcinoma of the head and neck were treated with single low doses of methotrexate (MTX) (30 mg/m2) iv, im, and orally in the form of commercial tablets. A randomized crossover design was employed. Plasma concentrations were measured by a modified EMIT assay over a period of 24 hours following each dose. The mean (+/- SD) parameters following iv MTX were as follows: total-body clearance, 124 (36) ml/minute; Vss, 0.56 (0.18) L/kg; V lambda, 0.69 (0.24) L/kg; and beta-half-life, 3.20 hours. The absolute systemic bioavailability of the oral tablets was 36% (+/- 10%). After im administration, the systemic bioavailability was 93% (+/- 14%). Dose-dependent gastrointestinal absorption is suggested as the mechanism for the low availability of the oral tablets. Administration of MTX by the oral route will require further study to determine the optimal method of dosing.

Absorption↗

PubMedDate not supplied

Pharmacologic antidotes to experimental doxorubicin skin toxicity: a suggested role for beta-adrenergic compounds.

Doxorubicin (ADM) skin toxicity is a serious complication of inadvertent perivenous drug infiltrations. In an attempt to attempt to identify possible antidotes, nine diverse pharmacologic agents were injected intradermally into the hair-free dorsum of BALB/c mice following an intradermal ADM dose of either 0.05 or 0.5 mg. Seven of the compounds were ineffective in reducing ADM-induced ulceration; the compounds included lidocaine, cimetidine, diphenhydramine, sodium heparin, hyaluronidase, N-acetylcysteine, and alpha-diphenhydramine, sodium heparin, hyaluronidase, N-acetylcysteine, and alpha-tocopherol. The latter five compounds actually increased ulceration induced by ADM (0.5 mg), especially N-acetylcysteine, which tripled the total toxic effect. Two opposing beta-adrenergic compounds, the antagonist propranolol and the agonist isoproterenol, reduced skin ulceration resulting from experimental treatment with intradermal ADM. A role for the beta-adrenergic receptor in mediating ADM-induced skin ulceration is suggested.

Animals↗

PubMedDate not supplied

Effect of doxorubicin on glutathione and glutathione-dependent enzymes in cultured rat heart cells.

The effect of doxorubicin (DOX) on heart cell glutathione (GSH)-based enzyme systems was investigated in a rat heart myocyte model. Cellular levels of GSH decreased commensurate with viability following exposure to DOX or to the unrelated alkaloidal cardiotoxin emetine. GSH depletion by L-buthionine sulfoximine (L-BSO) did not alter myocyte viability nor doxorubicin (DOX) dose-response. The nitrosourea carmustine (BCNU), which impairs GSH reductase activity, also did not alter DOX cardiotoxicity. Doxorubicin significantly increased glutathione-S-transferase (GST) activity in a time-dependent fashion. In contrast, selenium-dependent glutathione peroxidase activity was reduced by 50%. These findings demonstrate that lowered GSH or GSH reductase levels do not enhance DOX cardiotoxicity in vitro and suggest that DOX may be a substrate for GST.

Adenosine Triphosphate↗

PubMedDate not supplied

Clinical properties of yeast-derived versus Escherichia coli-derived granulocyte-macrophage colony-stimulating factor.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) can be expressed in yeast, bacteria, or mammalian cells. Expression in each system results in a protein that differs, to a varying extent, from native GM-CSF. Like the native protein, yeast-expressed GM-CSF is glycosylated and has 127 amino acids, but differs from native GM-CSF in molecular mass and in the substitution of leucine for proline at position 23. GM-CSF expressed in Escherichia coli bacteria is not glycosylated, has six fewer amino acids than the native protein, and an extra methionine at position 1. A review of laboratory studies shows that these differences in physiochemical properties result in variations in the pharmacokinetics, biologic activity, and immunogenicity of GM-CSF expressed in different host cells. These variations may lead to an increased clinical toxicity with GM-CSF expressed in E coli versus that produced in yeast. A total of 32 clinical trials were reviewed to determine the relative frequency of adverse events in patients treated with GM-CSF expressed in E coli versus that expressed in yeast. In general, the median reported frequency of adverse events was higher in patients treated with E coli-derived GM-CSF. The median frequencies of fluid retention, dyspnea, fever, myalgias/bone pain/joint pain, and rash were 8.3%, 13.4%, 21.7%, 16%, and 14.3%, respectively, in patients receiving GM-CSF expressed in yeast, versus 18.4%, 55.2%, 40.7%, 28.5%, and 12.5%, respectively, in patients treated with GM-CSF expressed in E coli. Thus data in the literature support the view that the GM-CSF expression system influences the pharmacokinetic properties, biologic activity, and clinical toxicity of GM-CSF.

Escherichia coli↗

PubMedDate not supplied

Pharmacology of the taxanes.

The taxanes paclitaxel and docetaxel are structurally similar, but they have different pharmacologic characteristics. Both bind to the beta-subunit of tubulin and affect microtubule polymerization. The cell cycle phases affected by the drugs are distinctly different; paclitaxel inhibits cell cycle traverse at the G2-M phase junction, and docetaxel produces maximum cell killing against cells in S phase. The drugs both undergo hepatic metabolism; however, the specific cytochrome P-450 (CYP) enzymes responsible for hydroxylation are CYP 2C8 for paclitaxel and CYP 3A4 for docetaxel. The cytotoxic effects of the taxanes are schedule dependent. For both drugs, longer durations of exposure increase cytotoxicity. Studies are being conducted to determine if prolonged exposure in cancer cell lines increases response rates in patients with sensitive tumors. The distinct mechanistic and metabolic differences between paclitaxel and docetaxel may influence clinical efficacy and safety in patients with cancer.

Animals↗