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M R Boyd

Publications and source records attributed to M R Boyd.

At least 199 records · Page 11Linked to original sources
PubMed1989

New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity.

We have developed an effective and optimally safe microculture method for rapid and convenient assay of the in vitro cytopathic effects of human immunodeficiency virus (HIV-1) on human lymphoblastoid or other suitable host cells. The assay procedure is applicable to the evaluation of drug effects on in vitro infections induced directly in cultured host cells by cell-free HIV-1 or by coculture with H9 cells chronically infected with HIV-1. The assay uses a newly developed tetrazolium reagent that is metabolically reduced by viable cells to yield a soluble, colored formazan product measurable by conventional colorimetric techniques. This simple microassay minimizes the number of plate manipulations typically required with other assay methods and, coupled with computerized data collection and analysis, facilitates large-scale screening of agents for potential antiviral activity. To support and enhance the discovery of new anti-HIV-1 agents, the National Cancer Institute is offering investigators worldwide the opportunity to submit new candidate agents for anti-HIV-1 screening with this method.

Antiviral Agents↗
PubMed1989

Evidence for prostanoid biosynthesis as a biochemical feature of certain subclasses of non-small cell carcinomas of the lung as determined in established cell lines derived from human lung tumors.

Detectable levels (greater than or equal to 0.2 pmol/10(6) cells) of one or more prostanoid species resultant to calcium ionophore A23187-induced biosynthesis from endogenous arachidonic acid were distributed in 28 cell lines derived from different histological classes of lung tumors as follows: large cell undifferentiated carcinoma (3 of 3 cell lines); adenosquamous carcinoma (1 of 2 cell lines); squamous cell carcinoma (0 of 2 cell lines); adenocarcinoma (9 of 10 cell lines); bronchioloalveolar cell carcinoma (2 of 2 cell lines); and small cell carcinoma (1 of 9 cell lines). Using the mean levels of 9 alpha,11 beta-prostaglandin F2, prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2, thromboxane B2 and 6-keto-prostaglandin F1 alpha as an index of prostaglandin H (PGH) synthase activity, the distribution in cell lines representative of the different histological classes of human lung tumors exhibiting PGH synthase activity exceeding mean values greater than or equal to 2 pmol/10(6) cells was as follows: large cell undifferentiated carcinoma (3 of 3 cell lines), adenosquamous carcinoma (1 of 2 cell lines), adenocarcinoma (8 of 10) cell lines), bronchioloalveolar cell carcinoma (2 of 2 cell lines) and small cell carcinoma (0 of 9 cell lines). Three different prostanoid species accumulated to mean levels greater than or equal to 2 pmol/10(6) cells. Prostaglandin E2 levels exceeded 2 pmol/10(6) cells in 14 of the 16 cell lines in which this prostanoid accumulated to detectable levels. Cumulative levels of prostaglandin F2 alpha exceeded 2 pmol/10(6) cells in 9 of the 15 cell lines in which prostaglandin F2 alpha reached detectable levels. Detectable levels of thromboxane B2 were observed in five cell lines with thromboxane B2 accumulation exceeding 2 pmol/10(6) cells in two of the five cell lines. 9 alpha,11 beta-prostaglandin F2 and 6-keto-prostaglandin F1 alpha accumulated to detectable levels in the culture medium of one cell line, while prostaglandin D2 accumulation to detectable levels was observed in two cell lines. Stimulation of cultured human lung tumor cells exhibiting PGH synthase activity greater than or equal to 2 pmol/10(6) cells in the presence of 10(-5) M exogenous arachidonic acid resulted in a 2- to 4-fold increase in the accumulation of individual prostanoids, while the inclusion of a 10(-5) M exogenous concentration of arachidonic acid failed to stimulate detectable prostanoid production in human lung tumor cells in which PGH synthase activity was not previously expressed.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma, Non-Small-Cell Lung↗
PubMed1989

Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties.

Potential oral prodrugs of the antiherpesvirus acyclonucleoside 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (1, BRL 39123) have been synthesized and evaluated for bioavailability of 1 in the blood of mice. Reduction of 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6-chloropurine (13) using ammonium formate and 10% palladium on carbon afforded the 2-aminopurine 14, which was hydrolyzed to the monoacetate 15 and to 2-amino-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purine (5). The 2-aminopurine 5 was subsequently converted to additional monoester (17, 21-23) and diester (16, 24) derivatives and to its di-O-isopropylidene derivative 18. Both 5 and its esters (14-17, 21, 22) and also 18 were well absorbed after oral administration and converted efficiently to 1, the diacetyl (14) and dipropionyl (16) esters providing concentrations of 1 in the blood that were more than 15-fold higher than those observed after dosing either 1 or its esters (25-27). Some 6-alkoxy-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines (8-10), the preparation of which has been reported previously, also showed improved absorption properties, but their conversion to 1 was less efficient than for the 2-aminopurine derivatives. On the basis of these results and subsequent experiments involving determinations of rates of conversion to 1 in the presence of rat and human tissue preparations, 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine (14, BRL 42810) was identified as the preferred prodrug of 1. Oral bioavailability studies in healthy human subjects confirmed 14 as an effective prodrug, and this compound is now being evaluated in clinical trials.

2-Aminopurine↗
PubMed1989

Selection of an oral prodrug (BRL 42810; famciclovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine; penciclovir].

The limited oral absorption in rodents of the antiherpesvirus agent 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine (BRL 39123 [penciclovir; British approved name]) prompted a search for oral prodrugs. The 6-deoxy derivative of penciclovir (BRL 42359) and the corresponding diacetyl and dipropionyl 6-deoxy derivatives (BRL 42810 [famciclovir; British approved name] and BRL 43599) were tested as oral prodrugs. The in vivo absorption (dose, 0.2 mmol/kg) and the conversion to the active compound, penciclovir, were determined in rats. Compared with the sodium salt of penciclovir given intravenously, the bioavailabilities of penciclovir from orally administered penciclovir, BRL 42359, famciclovir, and BRL 43599 were 1.5, 9, 41, and 27%, respectively. These prodrugs and 6-deoxyacyclovir were tested for stability in rat duodenal contents and for metabolism in rat intestinal wall homogenate, liver homogenate, and blood and in the corresponding human fluids and tissues. Famciclovir was much more stable than BRL 43599 in human duodenal contents (half-lives, greater than 2 h and 7 min, respectively) yet was efficiently converted to penciclovir by the tissue homogenates. The major metabolic pathway was by deacetylation followed by oxidation at the 6 position. The rate of oxidation was comparable to that of 6-deoxyacyclovir, which is known to be converted efficiently to acyclovir in humans. Famciclovir was selected for further evaluation and progression to studies in humans. These subsequent studies confirmed that, after oral dosing with famciclovir, more than half the dose was absorbed and rapidly converted to penciclovir.

2-Aminopurine↗
PubMed1988

Profiles of prostaglandin biosynthesis in sixteen established cell lines derived from human lung, colon, prostate, and ovarian tumors.

The profiles of prostanoid biosynthesis from endogenous arachidonic acid in 16 established cell lines derived from 4 histological classes of human carcinomas were determined by capillary gas chromatography-mass spectrometry. Detectable quantities of prostanoids were isolated from the culture medium of cell lines representative of the different histological classes of human tumors: colorectal adenocarcinomas (one of three cell lines); ovarian adenocarcinomas (one of three cell lines); prostate adenocarcinomas (zero of two cell lines); non-small cell carcinomas of the lung (four of five cell lines); and small cell carcinomas of the lung (zero of three cell lines). Prostaglandins E2 and F2 alpha were the only prostanoids synthesized in detectable quantities. Prostaglandin E2 biosynthesis (mean +/- SD), pmol/10(6) cells, n = 4) in cell lines exhibiting positive prostaglandin H synthase activity was: LoVo (colorectal adenocarcinoma, 0.4 +/- 0.1); A2780 (ovarian adenocarcinoma, 1.3 +/- 0.3); NCI-H322 (bronchioloalveolar cell carcinoma, 8.4 +/- 3.1); NCI-H358 (bronchioloalveolar cell carcinoma, 7.8 +/- 2.4); EKVX (adenocarcinoma of the lung, 21.3 +/- 5.5); and A427 (large cell undifferentiated carcinoma of the lung, 12.6 +/- 2.8). Prostaglandin F2 alpha production (pmol/10(6) cells +/- SD) was: LoVo (0.3 +/- 0.1); NCI-H322 (0.6 +/- 0.2); NCI-H358 (0.4 +/- 0.1); EKVX (1.8 +/- 0.4); and A427 (11.1 +/- 3.1). These findings suggest that within certain limitations cultured tumor cells provide simplified experimental systems for determination of prostaglandin biosynthetic characteristics of human tumors and that prostanoid biosynthesis may be particularly characteristic of certain non-small cell carcinomas of the lung.

Cell Line↗
PubMed1988

Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines.

We have previously described the application of an automated microculture tetrazolium assay (MTA) involving dimethyl sulfoxide solubilization of cellular-generated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-formazan to the in vitro assessment of drug effects on cell growth (M.C. Alley et al., Proc. Am. Assoc. Cancer Res., 27:389, 1986; M.C. Alley et al., Cancer Res. 48:589-601, 1988). There are several inherent disadvantages of this assay, including the safety hazard of personnel exposure to large quantities of dimethyl sulfoxide, the deleterious effects of this solvent on laboratory equipment, and the inefficient metabolism of MTT by some human cell lines. Recognition of these limitations prompted development of possible alternative MTAs utilizing a different tetrazolium reagent, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl] -2H- tetrazolium hydroxide (XTT), which is metabolically reduced in viable cells to a water-soluble formazan product. This reagent allows direct absorbance readings, therefore eliminating a solubilization step and shortening the microculture growth assay procedure. Most human tumor cell lines examined metabolized XTT less efficiently than MTT; however, the addition of phenazine methosulfate (PMS) markedly enhanced cellular reduction of XTT. In the presence of PMS, the XTT reagent yielded usable absorbance values for growth and drug sensitivity evaluations with a variety of cell lines. Depending on the metabolic reductive capacity of a given cell line, the optimal conditions for a 4-h XTT incubation assay were 50 micrograms of XTT and 0.15 to 0.4 microgram of PMS per well. Drug profiles obtained with representative human tumor cell lines for several standard compounds utilizing the XTT-PMS methodology were similar to the profiles obtained with MTT. Addition of PMS appeared to have little effect on the metabolism of MTT. The new XTT reagent thus provides for a simplified, in vitro cell growth assay with possible applicability to a variety of problems in cellular pharmacology and biology. However, the MTA using the XTT reagent still shares many of the limitations and potential pitfalls of MTT or other tetrazolium-based assays.

Azo Compounds↗
PubMed1988

Extrapulmonary, tissue-specific metastasis formation in nude mice injected with FEMX-I human melanoma cells.

FEMX-I human malignant melanoma cells, originating from a lymph node metastasis in a patient, uniquely and selectively produced extrapulmonary metastases after i.v. injection of cells prepared from xenografts into adult, nude mice. After a lag time of approximately 50 days, metastases were observed in s.c. sites at the back and front of the neck, and in axilla and inguinal regions. Tumor colony formation in lungs were never detected. The interscapular tumors showed a close relationship to brown fat, partly infiltrating this tissue, whereas the other s.c. tumors seemed to be localized to lymph nodes. Mesenterial and mediastinal lymph node metastases were frequently found, together with retroperitoneal tumors along the spine. The normal cells of the adrenal medulla were often replaced by melanoma cells, whereas the cortical tissue was not affected. The conclusion that FEMX-I cells possess an inherent ability for tissue-specific metastasis formation is supported by the metastatic pattern seen after i.p. and intrasplenic injection, as well as after inoculation of the cells in the footpads of the mice. The relatively slowly growing FEMX-I tumors showed the same differentiated morphology as the patient's tumor, independent of the site of growth and the number of passages in the animals. The FEMX-I tumor was easily established as a cell line in vitro. Such cells showed a strongly reduced metastatic capacity, indicating that the in vitro growth conditions had induced alterations in the FEMX-I cells influencing their ability to form site-specific metastases, changes that were shown to be reversible. It is suggested that structures on the surface of the tumor cells, as well as growth factors in the host tissues, may be of importance for the observed tissue specificity. The FEMX-I melanoma, which, as a human tumor in nude mice, has a unique metastatic pattern, offers possibilities for investigating mechanisms involved in site-specific metastasis formation, as well as for testing effects of antimetastatic, chemotherapeutic, and immunotherapeutic agents against human extrapulmonary micro- and macrometastases.

Animals↗
PubMed1988

Profiles of prostaglandin biosynthesis in normal lung and tumor tissue from lung cancer patients.

prostaglandin (PG) biosynthetic profiles from endogenous arachidonic acid were determined by capillary gas chromatography-mass spectrometry in matched fresh normal lung (NL) and lung cancer (LC) tissue fragments obtained from 42 individual LC patients at the time of diagnostic thoracotomy. The histological diagnoses represented were squamous cell carcinoma (N = 20), adenocarcinoma (N = 7), small cell carcinoma (N = 4), mixed cell carcinoma (N = 2), bronchioloalveolar cell carcinoma (N = 2), large cell undifferentiated carcinoma (N = 3), bronchial carcinoid (N = 1), and metastatic tumors (N = 3). When PG biosynthesis was determined in NL tissue separately, low mean levels of PGE2 and PGF2 alpha (less than 2 pmol/mg protein/15 min), intermediate levels of PGD2 and 6-keto-PGF1 alpha (6KPGF1 alpha) (2-7 pmol/mg protein/15 min), and high levels of thromboxane B2 (TXB2) (greater than 7 pmol/mg protein/15 min) were observed. There was no particular correlation with cigarette smoking history and PG biosynthesis in NL. When PG production in LC tissue was evaluated separately, high levels of PGE2, PGF2 alpha, and 6KPGF1 alpha as well as TXB2 and low levels of PGD2 were noted. In addition, LC tissue from cigarette smokers demonstrated elevated levels of PGE2, 6KPGF1 alpha, and TXB2 when compared to current nonsmokers with LC (P less than 0.05 in all instances). Simultaneous comparison of PG production in matched LC and NL tissue from individual patients indicated increased biosynthesis of PGE2 and PGF2 alpha and low levels of PGD2 in LC compared to NL tissue (P less than 0.05 in all instances; paired, two-tailed, Student's t test). Individual comparison of PG biosynthesis according to LC histological cell type revealed that PGE2 and PGF2 alpha were consistently elevated in all four common primary LC histological cell types, the only exception being large cell undifferentiated carcinoma. Interestingly, this latter LC histological cell type presented a unique profile with lower levels of PGE2 and PGD2 in LC than in NL tissue (P less than 0.05 in both instances). In addition, the biosynthesis of all 5 PGs studied was consistently higher in primary than metastatic adenocarcinomas of the lung (P less than 0.05 in all instances). No differences were observed in NL and LC tissue for the major LC histological cell types when PGD2, TXB2, or 6KPGF1 alpha biosyntheses were compared. These findings indicate that the profiles of PG biosynthesis in LC and NL tissue from individual patients may differ substantially. These differences may reflect, in part, contributions to the PG biosynthetic profile unique to malignant cells.

Arachidonic Acid↗
PubMed1988

Evidence for thromboxane biosynthesis in established cell lines derived from human lung adenocarcinomas.

Thromboxane B2 (TxB2) is the stable nonenzymatic hydrolysis product of thromboxane A2, a substance implicated in the initiation of the facilitative role of thrombocytes in the metastatic process. TxB2 was isolated from protein-free culture medium of cell lines Calu-3, Calu-6, A549, and A549/Asc-1, derived from human lung adenocarcinomas. TxB2 and other 20-carbon fatty acid cyclooxygenase products synthesized from exogenous and endogenous arachidonic acid were identified by their characteristic retention indices and fragmentation of electron-capture derivatives of unlabeled and deuterium-labeled products during combined capillary gas chromatography-mass spectrometry. TxB2 comprised 2 to 6% of 20-carbon fatty acid cyclooxygenase products biosynthesized from endogenous arachidonic acid in calcium ionophore A23187-stimulated Calu-6 and A549/Asc-1 cells and 16 to 25% of these products in Calu-3 and A549 cells. The addition of 10(-5) M exogenous arachidonic acid to the cultured cells resulted in a 2- to 3-fold increase in TxB2 and bisenoic prostanoid production with no significant alterations in the proportion of TxB2 production. Prostaglandin E2 and prostaglandin F2 alpha, two prostanoids that can be formed either enzymatically or nonenzymatically from prostaglandin H2, accounted for greater than 75% of isolatable 20-carbon fatty acid cyclooxygenase products synthesized from endogenous and exogenous arachidonic acid.

Adenocarcinoma↗
PubMed1988

Comparison of intrapulmonary, percutaneous intrathoracic, and subcutaneous models for the propagation of human pulmonary and nonpulmonary cancer cell lines in athymic nude mice.

The propagation efficiencies, growth patterns, histological appearances, and roentgenographic demonstration of tumors derived from six continuous human pulmonary tumor cell lines implanted intrathoracically (i.t.) and intrabronchially (i.b.) were compared with the conventional s.c. implantation method at three different tumor cell inocula (N = 184, i.b.; N = 185, i.t.; N = 180, s.c.). A tumor-related mortality of 100% was noted when the six different human lung tumor cell lines, including A549 adenocarcinoma, NCI-H125 adenosquamous carcinoma, NCI-H460 large cell undifferentiated carcinoma, NCI-H69 small cell carcinoma, and NCI-H358 and NCI-H322 bronchioloalveolar cell carcinomas, were implanted i.b. at a 1.0 x 10(6) tumor cell inoculum. A similar (92%) tumor-related mortality was observed when these same lung tumor cell lines were implanted i.t. at a 1.0 x 10(6) tumor cell inoculum (P greater than 0.10), whereas minimal (5%) tumor-related mortality was noted when cells from the six different cell lines were implanted s.c. (P less than 0.001). In addition, a dose-dependent, tumor-related mortality was noted for either i.t. or i.b. implantation when lower (1.0 x 10(5) or 1.0 x 10(4] tumor cell inocula were employed. Histological characteristics and growth patterns of tumors propagated employing the three implantation techniques were closely comparable for all three propagation methods and, in all instances, histological appearances of the tumors were representative of the current tumor cell lines from which they were derived. Approximately 30% of the lung tumors propagated i.t. grew in the chest wall and/or in the lung parenchyma as well as in the pleural space. In contrast, tumors propagated i.b. grew predominantly in the lung parenchyma. When five nonpulmonary human tumor cell lines (including U251 glioblastoma, LOX amelamontic melanoma, HT-29 colon adenocarcinoma, OVCAR 3 ovarian adenocarcinoma, and adriamycin-resistant MCF-7 breast adenocarcinoma) were propagated i.b. or i.t., there was considerable site-specific variability in tumor-related mortality depending on the tumor type. These data demonstrate that both the i.b. and i.t. models should be useful for the in vivo propagation and study of certain human pulmonary and nonpulmonary carcinomas as well as being advantageous for future studies of cancer biology and developmental therapeutics.

Animals↗
PubMed1988

Flavone-8-acetic acid augments systemic natural killer cell activity and synergizes with IL-2 for treatment of murine renal cancer.

The investigational drug flavone-8-acetic acid (FAA) potently augments NK activity in the spleen, liver, lungs, and peritoneum in a dose-dependent manner after i.v. or i.p. administration. Augmented NK activity peaks by 24 h after FAA injection and returns to normal after 6 days. Combined treatment of established murine renal cancer with FAA and rIL-2 results in up to 80% long term survival whereas FAA or rIL-2 alone were unable to induce any long term survivors. The optimal dose of rIL-2 required for use with FAA was in the range of 10,000 to 30,000 U/day. Further studies demonstrated that the regimen of FAA plus rIL-2 administration that was effective in treating established murine renal cancer also induced a more potent augmentation of NK activity than did either FAA or rIL-2 alone. Subsequent studies revealed that the therapeutic effectiveness of FAA plus rIL-2 was significantly reduced when tumor-bearing mice were treated with anti-asialo GM1 serum. These results are consistent with a role for augmented NK activity in the therapeutic effects of FAA plus rIL-2 murine renal cancer. In addition, these studies demonstrate that FAA and rIL-2 is a useful approach for cancer treatment in that subtoxic doses of rIL-2 can be used and significant anti-tumor efficacy occurs even without accompanying adoptive immunotherapy.

Animals↗
PubMed1988

Pulmonary toxicity of doxorubicin administered by in situ isolated lung perfusion in dogs.

The possibility of in situ isolated lung perfusion as a means of treating nonresectable pulmonary cancers unresponsive to conventional chemotherapy has been investigated. The present study has examined the biochemical and morphological effects of in situ isolated lung perfusion in dogs with doxorubicin (DOX). A dose related complication was seen in the animals following lung perfusion. Lactate dehydrogenase (LDH) activity in the perfusate increased as dose was increased, indicating tissue damage during the perfusion. Up to 7 days postperfusion, marked changes were seen in the serum protein concentrations although these were independent of doxorubicin concentrations. Serum lactate dehydrogenase showed a dose dependent increase 2 hour and 1 day after the lung perfusion. Plasma angiotensin converting enzyme activities up to 14 days postperfusion suggested that DOX produced pulmonary endothelial cell injury at higher drug doses. Histopathologic examination of the lungs from dogs receiving the highest concentrations of drug indicated that necrosis of arterial endothelia and alveolar epithelia accompanied by periarterial edema, subplural edema and emphysema of the lungs were the probable causes of acute animal mortality. The study has demonstrated that doxorubicin produces dose-dependent damage to the pulmonary tissue. However, the observed injury only appeared life-threatening at perfusate drug concentrations in excess of 20 nmol/ml. In situ lung perfusion for the treatment of unresectable pulmonary tumors may be clinically applicable.

Alanine Transaminase↗
PubMed1988

Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay.

For the past 30 years strategies for the preclinical discovery and development of potential anticancer agents have been based largely upon the testing of agents in mice bearing transplantable leukemias and solid tumors derived from a limited number of murine as well as human sources. The feasibility of implementing an alternate approach, namely combined in vitro/in vivo screening for selective cytotoxicity among panels of human tumor cell lines derived from a broad spectrum of human solid tumors is under investigation. A group of 30 cell lines acquired from a variety of sources and representing 8 lung cancer pathologies as well as 76 cell lines representing 10 other categories of human cancer (carcinomas of colon, breast, kidney, prostate, ovary, head and neck; glioma; leukemia; melanoma; and sarcoma) have exhibited acceptable growth characteristics and suitable colorimetric profiles in a single, standard culture medium. Measurements of in vitro growth in microculture wells by cell-mediated reduction of tetrazolium showed excellent correlation (0.89 less than r2 less than 0.98) with measurements of cellular protein in adherent cell line cultures as well as viable cell count in suspension cell line cultures (0.94 less than r2 less than 0.99). Since the microculture tetrazolium assay provides sensitive and reproducible indices of growth as well as drug sensitivity in individual cell lines over the course of multiple passages and several months' cultivation, it appears suitable for initial-stage in vitro drug screening.

Antineoplastic Agents↗
PubMed1988

Comparative toxicity and renal distribution of the platinum analogs tetraplatin, CHIP, and cisplatin at equimolar doses in the Fischer 344 rat.

Tetraplatin [tetrachloro(dl-trans)1,2-diaminocyclohexane platinum(IV), NSC-363812] is a new anticancer platinum drug analog targeted for clinical development because of its effectiveness against cisplatin-resistant tumor cell lines and its improved formulation. The toxicity of tetraplatin was compared at equimolar doses to that of cisplatin [cis-diamminedichlorophatinum(II)] and CHIP [cis-dichloro,trans-dihydroxybis-isopropylamine platinum(IV), NSC-256927]. Adult male Fischer 344 rats received an iv bolus injection of 6.7, 13.3, 26.7, or 53.3 mumol/kg of one of these drugs in saline and were killed on Day 1, 3, 5, 8, or 15 postinjection for assessment of toxicity with emphasis on evaluation of nephrotoxicity. Rats to be killed on Day 15 were housed in metabolism cages for daily urine collection. Tetraplatin was less nephrotoxic than cisplatin at equimolar doses; CHIP was not nephrotoxic at these doses. Renal platinum contents were similar after all three drugs and did not appear to be related directly to the nephrotoxicity. Nephrotoxicity was detected 4-5 days after 6.7 mumol/kg cisplatin, was localized to the corticomedullary junction, and progressed with time and dose. Tetraplatin-induced alterations of renal function were first observed after 13.4 mumol/kg on Day 4 as an elevation of urine volume (up to 10-fold) and a smaller elevation of urinary glucose excretion. Tetraplatin lesions were localized in the mid- and outer cortex and, even at the highest dose, were less severe than those observed with cisplatin. There were other prominent toxic effects of tetraplatin, such as gastrointestinal toxicity and myelosuppression, which indicate that factors other than comparative nephrotoxicity may impact the clinical potential of this new agent.

Animals↗
PubMed1988

In vivo biochemical indices of nephrotoxicity of platinum analogs tetraplatin, CHIP, and cisplatin in the Fischer 344 rat.

In vivo biochemical indices of nephrotoxicity were investigated in Fischer 344 rats treated with a new platinum analog, tetraplatin [tetrachloro(dl-trans)1,2-diaminocyclohexane platinum(IV), NSC-363812], in comparison with rats receiving equimolar dosages of cisplatin and CHIP [cis-dichloro,trans-dihydroxybis-isopropylamine platinum(IV), NSC-256927]. The goals of this study were to assess the comparative nephrotoxicities and to determine which battery of tests might be useful for the assessment of platinum analog-induced nephrotoxicity in future clinical investigations of these drugs. An iv bolus injection of 6.7, 13.3, 26.7, and 53.3 mumol/kg of each drug in saline was administered and assessment of biochemical parameters was conducted for 15 days postinjection. A combination of urinary enzyme and protein excretion rates along with blood urea nitrogen (BUN) determinations was used to assess the nephrotoxicity of these compounds. At equimolar dosages, tetraplatin appeared to be less nephrotoxic than cisplatin, and CHIP was not nephrotoxic. At all dosages tested, cisplatin increased the rate of urinary excretion of protein, lactate dehydrogenase (LDH), and N-acetylglucosaminidase (NAG) between Days 1 and 5. Tetraplatin did not affect these parameters until the 13.3 mumol/kg dosage. Cisplatin had little effect on the excretion rates of the brush border enzymes alkaline phosphatase and maltase, whereas tetraplatin caused an initial elevation with delayed onset of peak excretion rates at 8 days postinjection. Changes in BUN were not evident until after the 13.3 mumol/kg dosage of cisplatin and the 26.7 mumol/kg dosage of tetraplatin. BUN was useful for ranking the relative toxicities of the three compounds tested, but was not as sensitive in detecting the onset of injury that correlated with early histopathological changes. Tetraplatin appeared to be less nephrotoxic than cisplatin on an equimolar basis and the specific manifestations of its toxicity were different from those observed with cisplatin. Urinary excretion rates for LDH, NAG, and protein proved to be sensitive indicators of platinum analog-induced nephrotoxicity. These indices, combined with BUN determinations and functional assessments, facilitated comparisons of the nephrotoxicity induced by cisplatin and tetraplatin in rats.

Animals↗
PubMed1988

Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) in animals.

The antiviral activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) was assessed in several animal models of herpes simplex virus (HSV) infection. BRL 39123 was as active as acyclovir (ACV) when applied topically to guinea pigs with a cutaneous HSV type 1 (HSV-1) infection and was also active topically in an HSV-2 genital infection. Before systemic administration to infected animals, BRL 39123 and ACV were administered orally and subcutaneously to mice, and the blood was assayed for each compound by high-pressure liquid chromatography. When given systemically to mice infected cutaneously with HSV-1, BRL 39123 was as active as ACV. In mice infected intranasally with HSV-1 or HSV-2, single daily subcutaneous doses of BRL 39123 were more effective than equivalent treatment with ACV, reflecting the more persistent activity seen in cell culture and a more stable triphosphate within the infected cell. When the compounds were supplied in drinking water for this infection, BRL 39123 and ACV had similar potencies against HSV-1, although ACV was more active against an HSV-2 infection than BRL 39123 was. In mice infected intraperitoneally with HSV-1, BRL 39123 was 10-fold more potent than ACV and a single dose of BRL 39123 reduced virus replication within the peritoneal cavity more effectively than 3 doses of ACV given 1, 5, and 20 h after infection. Although BRL 39123 failed to eradicate the virus from mice latently infected with HSV-1, treatment initiated 5 h after infection of the ear pinna reduced the numbers of mice that developed latent infections.

Acyclovir↗
PubMed1987

Metabolism of arachidonic acid in human lung cancer cell lines.

The metabolism of arachidonic acid (AA) was studied in two pulmonary bronchioloalveolar-carcinoma cell lines (NCI-H322 and NCI-H358) and two small cell lung carcinoma cell lines (NCI-H69 and NCI-H128). Exogenous AA was metabolized only in the NCI-H322 and NCI-H358 cells. There was no detectable metabolism of AA in NCI-H69 or NCI-H128 cells, either in the presence or the absence of the calcium ionophore A23187. The major metabolite of AA isolated from both NCI-H322 and NCI-H358 cells was prostaglandin E2 (PGE2). Prostaglandin endoperoxide synthase activities, expressed as immunoreactive PGE2 (pmol/min/mg protein), were 10.3 +/- 0.28 (SD) and 4.8 +/- 0.48 in NCI-H358 and NCI-H322 cells, respectively. The rate of production of PGE2 by both NCI-H358 and NCI-H322 cells was linear up to 10 min. Production of PGE2 in both cell lines was dependent upon substrate concentration and was maximal above 17 microM AA. Moreover, PGE2 did not undergo further metabolism by either the NCI-H358 or the NCI-H322 cells. Aspirin (0.1 mM), a cyclooxygenase inhibitor, decreased PGE2 production by 77 and 60% in NCI-H358 and NCI-H322 cells, respectively. In the presence of exogenous AA the calcium ionophore, A23187 (20 microM), stimulated PGE2 production in NCI-H322 cells by almost 2-fold, although it did not affect PGE2 production in the NCI-H358 cells. In contrast, A23187 stimulated the endogenous production of PGE2 in both NCI-H322 and NCI-H358 cells by 4- and 9-fold respectively. In addition, both the NCI-H358 and NCI-H322 cell lines were susceptible to the cytotoxic effects of the anticancer agent mitoxantrone in both a time and concentration dependent manner. In contrast, the two cell lines lacking detectable prostaglandin synthesis activity, NCI-H69 and NCI-H128 were unaffected by treatment with mitoxantrone. These results illustrate that there are major differences in the abilities of human lung cancer cell lines to biosynthesize and release PGE2. It is conceivable that such differences might have exploitable diagnostic and/or therapeutic implications.

Adenocarcinoma, Bronchiolo-Alveolar↗