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Biomedical subjects

S D Harrison

Publications and source records attributed to S D Harrison.

At least 55 records · Page 3Linked to original sources
PubMed1991

Massive tricuspid regurgitation identified on renal flow scintigraphy.

A Tc-99m glucoheptonate renal flow study performed in a patient with chronic renal insufficiency and worsening congestive heart failure demonstrated evidence of massive tricuspid regurgitation, with activity appearing in a markedly dilated inferior vena cava within 4 seconds of the tracer bolus entering the right ventricle. Autopsy subsequently confirmed the scintigraphic findings, demonstrating an incompetent tricuspid valve secondary to immobilization of the posterior leaflet as a result of adhesions from a longstanding right ventricular pacemaker wire.

Aged↗
PubMed1990

Antitumor activity of ethyl 5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido [3,4-b]pyrazin-7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) against selected tumor systems in culture and in mice.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin- 7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) was evaluated for antitumor activity against a spectrum of tumor systems in culture and in mice. NSC 370147 was cytotoxic to a variety of mouse and human cell lines at nanomolar concentrations. The compound exhibited good in vivo antitumor activity against several murine tumors (P388 and L1210 leukemia, colon 11/A and 36, mammary 16/C, and M5076 sarcoma). Activity was largely independent of route of administration but favored a prolonged treatment schedule. NSC 370147 was as active against murine leukemia sublines resistant to Adriamycin, amsacrine, vincristine, melphalan, cisplatin, methotrexate, and CI-920 (a topoisomerase II inhibitor) as against the corresponding parental lines. Only the 1-beta-D-arabinofuranosylcytosine-resistant P388 subline exhibited any cross-resistance to NSC 370147. NSC 370147 has a spectrum of activity similar to that of vincristine and, unlike vincristine, is active against multidrug-resistant cell lines. Therefore, NSC 370147 is a candidate for clinical trial because of its favorable activity compared to vincristine, its effectiveness against multidrug-resistant cells, and its retention of activity for p.o. administration.

Animals↗
PubMed1990

The tramtrack gene encodes a Drosophila finger protein that interacts with the ftz transcriptional regulatory region and shows a novel embryonic expression pattern.

We have identified a Drosophila zinc-finger protein, which binds to a number of sites in the transcriptional control regions of the pair-rule gene fushi-tarazu (ftz). The expression pattern of the mRNA that encodes this protein is essentially complementary to that of ftz both prior to blastoderm formation and during germband extension. We propose that the protein may function by repressing inappropriate segmentation gene transcription during embryogenesis. The gene encoding this ftz promoter-binding protein has been named tramtrack (ttk).

Amino Acid Sequence↗
PubMed1990

Schedule dependence, activity against natural metastases, and cross-resistance of pyrazine diazohydroxide (sodium salt, NSC 361456) in preclinical models in vivo.

Pyrazine diazohydroxide (sodium salt, NSC 361456; PZDH) is a new antitumor drug with relatively broad activity in initial evaluations against murine leukemias, solid tumors, and two human tumor xenografts in vivo. The present studies were designed to address questions about PZDH activity on different treatment schedules, its activity against metastases, and the extent of its cross-resistance with established drugs. Human LOX amelanotic melanoma xenografts in athymic mice were used to explore schedule dependence and activity against natural metastases, and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. Single-dose treatment and prolonged treatment provided equivalent therapeutic responses to PZDH by both the i.p. and i.v. routes in the i.p. LOX model. A s.c. LOX model resulting in spontaneous pulmonary metastases was adapted for bioassay and quantitation of the numbers of LOX cells killed by PZDH among both primary and metastatic cell populations. It was demonstrated that PZDH afforded about 2-log10 orders of magnitude greater cell kill among pulmonary metastases than against primary s.c. LOX tumors in the same mouse. Murine leukemias resistant to doxorubicin (ADR), vincristine (VCR), cisplatin (DDPt), methotrexate (MTX), N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), and cyclophosphamide (CPA) were not cross-resistant to PZDH. However, both P388 and L1210 leukemia sublines resistant to melphalan (L-PAM) were cross-resistant to PZDH, suggesting that patients previously treated with L-PAM might have less likelihood of response to PZDH than those who had had no opportunity to develop L-PAM resistance. Although these observations should not be applied to clinical studies without due caution, they support clinical evaluation of PZDH as well as continued investigation of its molecular pharmacology.

Animals↗
PubMed1990

Evaluation of combinations of interferons and cytotoxic drugs in murine tumor models in vivo.

This investigation was conducted to provide preclinical in vivo tumor response data collected under standardized conditions with a range of clinically useful drugs combined with type I (alpha/beta) or type II (gamma) interferon. Murine tumor models used were P388 leukemia, Meth A sarcoma, and B16 melanoma. Eleven cytotoxic drugs were studied. Interferon combinations with cytosine arabinoside provided consistent indications of activity greater than that of the respective single agents. Doxorubicin and cisplatin each prolonged the time to treatment failure, relative to single-agent results, when they were combined with gamma-interferon in the Meth A and B16 models. Interferon combinations with methotrexate, 6-mercaptopurine, 6-thioguanine, ampligen, suramin, 5-fluorouracil, cyclophosphamide, and vinblastine yielded no evidence of any positive therapeutic interactions under the conditions of this study.

Animals↗
PubMed1989

Preclinical antitumor activity of an alpha-picoline derivative, penclomedine (NSC 338720), on human and murine tumors.

Penclomedine, a synthetic alpha-picoline derivative, was identified as a potential antitumor agent in the P388 leukemia prescreen of the National Cancer Institute. Upon further evaluation in the National Cancer Institute in vivo tumor panel, the compound demonstrated good activity against two breast tumors. A single i.p. dose or five daily doses caused partial regressions of advanced-stage s.c. implanted mouse CD8F1 mammary adenocarcinomas. Also, penclomedine administered i.p. on Days 1,5, and 9 caused regression of the human MX-1 mammary carcinoma implanted under the renal capsule of athymic mice. In contrast, penclomedine demonstrated only marginal to moderate activity against the i.p. implanted L1210 leukemia and M5076 sarcoma and was inactive in three additional non-breast tumor models (i.p. B16 melanoma, i.v. Lewis lung carcinoma, and s.c. colon adenocarcinoma 38). Penclomedine administered p.o. and i.p. was equally effective against the subrenal capsule MX-1. Doses given p.o. every fourth day caused complete regression of 39 of 40 advanced-stage s.c. implanted MX-1 tumors but were much less effective against human H82 small cell lung carcinomas (13 of 80 complete regressions). Penclomedine p.o. also inhibited growth of the human MCF-7 and mouse 16/C breast adenocarcinomas. Further studies to support the development of penclomedine to clinical trial are in progress.

Animals↗
PubMed1989

Antitumor activity of 2-chloroethyl (methylsulfonyl)methanesulfonate (clomesone, NSC 33847) against selected tumor systems in mice.

Clomesone was evaluated for antitumor activity against a spectrum of animal tumor models. Clomesone exhibited significant antitumor activity against the murine L1210 leukemia implanted i.p., s.c., and intracerebrally (i.c.). Activity against s.c.-implanted tumor was largely independent of schedule and route of administration. Therapeutically optimal single-dose treatment (for tumored mice) was less toxic to nontumored mice than therapeutically optimal prolonged treatment. Clomesone also exhibited activity against other murine tumors (P388 leukemia, B16 melanoma, Lewis lung carcinoma, and M5076 sarcoma). It was active against P388 leukemia sublines resistant to cyclophosphamide, L-phenylalanine mustard, and cis-diamminedichloroplatinum(II). No activity was observed against a P388 subline resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea or against Ridgway osteogenic sarcoma, a nitrosourea-resistant murine solid tumor. Clomesone is generally as effective as the chloroethylnitrosoureas against experimental tumor models. Since clomesone does not have the hydroxyethylating and carbamoylating activities of the chloroethylnitrosoureas (which do not appear to contribute to antitumor activity), it would likely be a more toxicologically selective compound. It may prove to be less carcinogenic than the chloroethylnitrosoureas, and it may contribute less target organ toxicity and less interference with the actions of other drugs when used in combinations.

Animals↗
PubMed1988

Identification of the binding sites for potential regulatory proteins in the upstream enhancer element of the Drosophila fushi tarazu gene.

With a view to identifying proteins that regulate the expression of the Drosophila ftz gene we have sequenced its enhancer-like upstream element (USE) and determined the binding sites for embryonic nuclear proteins within this region by in vitro DNAaseI footprinting. We find that greater than 50% of this element is bound by nuclear protein. By footprinting and gel-retardation studies in embryonic extracts from different developmental stages, we have characterised a number of USE/protein complexes whose nature alters in concert with changes in the ftz expression pattern, suggesting that these USE-binding proteins may be involved in the regulation of gene activity. In some cases this suggestion is substantiated by the observation that the protected DNA sequences show homology to the binding sites for ftz regulating DNA-binding proteins such as the pair-rule gene product even-skipped.

Animals↗
PubMed1988

Preclinical antitumor activity of batracylin (NSC 320846).

Batracylin (NSC 320846, BAY H 2049), given ip on days 2 and 9 at a dose 400 mg/kg, inhibited tumor growth completely in 80-100% of mice with early-stage colon adenocarcinoma 38. Therapeutic efficacy against this subcutaneously implanted tumor was retained upon oral administration of Batracylin although, compared to ip treatment, larger doses were required. Batracylin also caused regression of advanced (400 mg) colon 38 tumors. Only modest activity was observed for this compound against P388 leukemia, but P388 sublines with acquired resistance to either adriamycin or cisplatin demonstrated collateral sensitivity. Batracylin currently is undergoing toxicological evaluation by NCI prior to clinical trials.

Adenocarcinoma↗
PubMed1987

Evaluation of the antitumor activity of recombinant human gamma-interferon employing human melanoma xenografts in athymic nude mice.

Three human melanoma cell lines (G-361, HT-144, and SK-MEL-3) that were highly sensitive to growth inhibition in vitro by recombinant human interferon (rHuIFN-gamma) were adapted to grow as s.c. xenografts in athymic nude mice. Take rates were greater than 90% for all three tumors, with in vivo doubling times of 15, 4, and 15 days for G-361, HT-144, and SK-MEL-3, respectively. Commencing 3 days posttumor implantation mice were treated with daily s.c. injections of rHuIFN-gamma for 30 days over a dose range of 2.4-326 megaunits/mouse/day at a site distinct from the tumor implant. Tumors were measured twice weekly and mice were observed daily for deaths and morbidity until day 60 postimplantation. No apparent antitumor activity was observed in either the G-361 or HT-144 tumors at any dose despite the achievement of high rHuIFN-gamma blood levels. Intralesional treatment of the HT-144 xenograft with rHuIFN-gamma at 240 megaunits/mouse/day did not significantly retard tumor growth or increase lifespan. However, the SK-MEL-3 tumor showed a significant response at the 326-megaunit dose as noted by a tumor growth delay of 11.8 days in treated versus control animals and by an increased number of 60-day survivors. The tumor growth suppression appeared to be greater during the treatment period than during the subsequent observation period. Other experiments employing 326, 530, and 860 megaunits rHuIFN-gamma/mouse/day in mice bearing the SK-MEL-3 tumor demonstrated tumor growth delays of 4.2, 4.8, and 19.8 days, respectively, suggesting a dose response. These data support the conclusions that (a) in vitro antiproliferative activity of rHuIFN-gamma is not necessarily predictive of in vivo efficacy; and (b) relatively high doses of rHuIFN-gamma appear to be required for demonstrating an in vivo antitumor effect in this model.

Animals↗
PubMed1987

Preclinical antitumor activity and pharmacological properties of deoxyspergualin.

A new antibiotic, deoxyspergualin (DSG), demonstrated antitumor activity against L1210 leukemia in mice. The life span of mice bearing either i.p. or s.c.-implanted L1210 increased greater than 150% following i.p. administration of 25 mg/kg DSG on days 1-9. Activity obtained with i.p. bolus treatments was schedule dependent. The tumor burden in mice bearing the s.c. implanted L1210 was reduced by 4-6 log10 units at the end of treatment when DSG was administered every 3 h for 8 injections on days 1, 5, and 9. By contrast, single injections of DSG on days 1, 5, and 9 allowed the tumor burden to increase at least 100-fold during treatment and daily single injections for 9 days reduced the tumor burden by 2 log10 units. The therapeutic advantage for i.p.-implanted L1210 of maintaining plasma concentrations of DSG was indicated further by infusion studies using s.c.-implanted Alzet osmotic pumps. Tumor burden was reduced by 3.5 and 6 log10 units following s.c. bolus treatments every 3 h on day 1 and a 24 h-infusion, respectively. The optimal infusion time for an infusion rate in mice of 179 mg/kg/day appeared to be 72 h. Pharmacokinetic studies following bolus i.v. injection revealed a rapid plasma clearance of parent drug (20.8 ml/min/kg) and a beta half-life of approximately 12 min. The bolus dose kinetics was used to predict the steady state plasma concentrations resulting from s.c. infusion; good agreement was observed between predicted values and experimental results. Based on these preclinical data, DSG has been developed to clinical trial. Initial Phase I protocols involve a 120-h infusion schedule.

Administration, Oral↗
PubMed1987

Arabinosyl-5-azacytosine: a novel nucleoside entering clinical trials.

Arabinosyl-5-azacytosine is a new compound which has been selected by the Division of Cancer Treatment, National Cancer Institute for clinical development as an antineoplastic agent based on its high degree of activity against a broad range of tumor types in preclinical studies. Therapeutic activity has been observed against murine and human leukemias, transplantable murine solid tumors, and human tumor xenografts. Arabinosyl-5-azacytosine exhibited a broader spectrum of activity against human solid tumors than cytosine arabinoside. Arabinosyl-5-azacytosine is phosphorylated to the nucleotide level by deoxycytidine kinase. Upon further anabolism to the triphosphate level, it can be incorporated into DNA. The mechanism of cytotoxicity is thought to be related to inhibition of DNA synthesis. Leukemic and solid tumor cell lines that are resistant to cytosine arabinoside due to deletion of deoxycytidine kinase activity are cross-resistant to arabinosyl-5-azacytosine. Unlike cytosine arabinoside, arabinosyl-5-azacytosine does not readily undergo deamination. Schedule dependence has been demonstrated in mice bearing L1210 leukemia, with superior activity seen with multiple doses administered on each treatment day compared to administration of larger but less frequently administered doses. From preliminary data in solid tumor models, however, antitumor activity did not appear to be superior with continuous infusion compared to that observed on a bolus schedule. Preclinical toxicology studies indicated that the bone marrow and gastrointestinal tract were the main target organs. A single large dose of arabinosyl-5-azacytosine could be tolerated by both mice and dogs. When administered as a continuous infusion, the toxicity was related to both the dose and duration of exposure, suggesting that toxicity resulted from a critical time above a threshold concentration as opposed to the total area under the concentration-time curve. Phase I clinical trials have been initiated to determine the maximum tolerated dose on a low dose continuous infusion schedule for 72 hours and also on a high dose short infusion daily times five schedule.

Antiviral Agents↗
PubMed1987

Cross-resistance of drug-resistant murine leukemias to deoxyspergualin (NSC 356894) in vivo.

Deoxyspergualin, the 15-deoxy derivative of the antibiotic spergualin, is a novel guanidino analog structurally related to spermine. Deoxyspergualin has significant activity in selected experimental tumor models, and clinical trials have been initiated. Described here are in vivo evaluations of the therapeutic activity of deoxyspergualin against murine leukemia lines specifically resistant to eight clinically useful antitumor drugs. These were P388 lines resistant to doxorubicin, vincristine, L-phenylalanine mustard, cisplatin, ara-C, and methotrexate and L1210 lines resistant to 5-FU, L-phenylalanine mustard, and cyclophosphamide. Sensitivity to deoxyspergualin was evaluated in parallel comparisons of each resistant leukemia to the sensitive line from which it had been derived. All experiments were repeated at least once for confirmation of results. Responses were quantitated in terms of the change in tumor cell numbers from the beginning of treatment to the end of treatment as estimated from the median survival times of dying mice. The results indicated that P388 leukemia resistant to cisplatin (P388/DDPt) was cross-resistant to deoxyspergualin. No cross-resistance was observed in leukemias resistant to doxorubicin, vincristine, ara-C, methotrexate, or cyclophosphamide. L1210 resistant to 5-FU (L1210/5-FU) was collaterally sensitive to deoxyspergualin. Although cross-resistance was also observed in P388/L-PAM, L1210/L-PAM retained sensitivity to deoxyspergualin. Total glutathione concentrations in P388/L-PAM and L1210/L-PAM provided no apparent explanation for this unexpected result. It may be tentatively concluded that resistance to cisplatin, L-PAM, or other DNA alkylators or cross-linkers may increase the potential for cross-resistance to deoxyspergualin. This conclusion requires verification with additional alkylating agents, with drug-resistant human tumor cell lines, and with prospective clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Evaluation of trans-tetrachloro-1,2-diaminocyclohexane platinum (IV) in murine leukemia L1210 resistant and sensitive to cis-diamminedichloroplatinum (II).

trans-Tetrachloro-1,2-diaminocyclohexane platinum (IV) (tetraplatin) was therapeutically effective in mice bearing leukemia L1210 resistant (L1210/DDPt) or sensitive (L1210/0) to cis-diamminedichloroplatinum (II) (cisplatin). Furthermore, the sensitivity of cultured L1210/DDPt and L1210/0 cell populations to tetraplatin, cisplatin, and dichloro-trans-dihydroxyisopropylamine platinum (IV) (CHIP) was a function of the concentrations used for each compound. The relative degree of sensitivity between cultured L1210/DDPt and L1210/0 cells for each compound on the basis of the LC99 (the concentration of each compound required to reduce the number of viable cells by 99% in each cell line) was 3-fold for cisplatin, 2-fold for tetraplatin, and 3-fold for CHIP; thus the cultured L1210/0 cells exhibited a greater degree of sensitivity than the L1210/DDPt cells to the platinum compounds. The data indicate that if reduction of platinum IV compounds to platinum II compounds or metabolites is required for antitumor activity, then the cultured L1210 cells are capable of this bioreduction independently of any host factors.

Animals↗
PubMed1986

Therapeutic synergism of tiazofurin and selected antitumor drugs against sensitive and resistant P388 leukemia in mice.

Tiazofurin is a synthetic "C" nucleoside analogue with a promising spectrum of experimental antitumor activity and a relatively novel mechanism of action. Previous work in our laboratories had revealed indications of collateral sensitivity and therapeutic synergism for selected murine tumor models treated with tiazofurin alone or in combination with an antimetabolite or an alkylating agent. Elucidation by others of biochemical indicators of tiazofurin activity provided the rationale for extending our studies to include the tiazofurin combinations reported here. Young, adult, female, BALB/c X DBA/2 F1 mice bearing body burdens of about 4 X 10(7) cells at the start of treatment were used. Cells were implanted either i.p. or s.c. Tiazofurin plus cisplatin or the 5'-palmitate of 1-beta-D-arabinofuranosylcytosine (ara-C) was evaluated against the parent P388/O leukemia line. Tiazofurin plus 6-thioguanine was evaluated against the ara-C-resistant P388. All drug treatments were i.p. injections given daily for 9 days. The experimental design permitted comparison of optimal nontoxic single-agent and two-drug combination regimens on the basis of the estimated log10 change in tumor cell burden at the end of treatment. Concurrent untreated control mice bearing tumor burdens ranging from approximately one to 10(7) cells permitted estimates of cells surviving treatment. Optimal treatment with each of these combinations afforded tumor burden reductions that were greater by 1 to 7 orders of magnitude than the effects of the respective single agents. Optimal single-agent and combination dosages (mg per kg per dose) were as follows: tiazofurin, 500; cisplatin, 2.0; the 5'-palmitate of ara-C, 25; 6-thioguanine, 0.8; tiazofurin, 330 plus cisplatin, 0.58; tiazofurin, 220 plus the 5'-palmitate of ara-C, 20; tiazofurin, 100 plus 6-thioguanine, 0.8. The observed therapeutic synergism of these drugs with tiazofurin in animal models suggests the possibility that treatment with tiazofurin combinations may yield clinical results superior to those obtained with the single agents alone. Therapeutic synergism can be most readily maximized when biochemical markers of drug action are available to provide appropriate clinical-laboratory correlations. Extension of these approaches to the use of tiazofurin, for which biochemical markers and experimental combination chemotherapy leads are now available, would support the rational clinical development of tiazofurin combinations.

Animals↗
PubMed1985

Effect of nitrosoureas on calmodulin activity in vitro and in mouse intestine in vivo.

The effects of BCNU, CCNU, methyl-CCNU, streptozotocin, and chlorozotocin on calmodulin activity were studied in vitro and in vivo. Preincubation of BCNU, CCNU, and methyl-CCNU with calmodulin produced a concentration-dependent inhibition of in vitro calmodulin activity expressed as stimulation of cyclic nucleotide phosphodiesterase. Cyclohexylisocyanate produced a similar inhibition. Streptozotocin and chlorozotocin had no effect. Calmodulin inhibition by methyl-CCNU was dependent on the concentration of calcium in the preincubation mixture. Administration of methyl-CCNU or chlorozotocin IP to CF1 mice produced a dose-dependent inhibition of calmodulin activity in the small intestine. Methyl-CCNU produced a significant decrease in intestinal calmodulin activity as early as 1 h after treatment, an effect that persisted up to 52 h. Morphologic changes in the intestinal crypt epithelial cells were evident between 27 h and 5 days after treatment, but not earlier than 27 h. Renal and testicular calmodulin activity and morphology were unaffected. Although it was not possible to correlate the extent of calmodulin inhibition with severity of the intestinal lesions, the data suggested a relationship between reduced activity of calmodulin in a tissue and the ultimate appearance of lesions. This apparent interaction between an antitumor drug and calmodulin in vivo could have multiple implications for cancer chemotherapy.

Animals↗