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T S Lawrence

Publications and source records attributed to T S Lawrence.

At least 127 records · Page 7Linked to original sources
PubMed1990

A comparison of 131I-labeled monoclonal antibody 17-1A treatment to external beam irradiation on the growth of LS174T human colon carcinoma xenografts.

Inhibition of growth of LS174T human colon cancer xenografts in athymic nude mice due to 131I-labeled MoAb 17-1A treatment was compared to inhibition due to different single doses of 60Co external radiation. From those data, conditions which produced equivalent radiobiological end points could be identified and compared to dose estimates calculated using a technique analogous to the Medical Internal Radiation Dose (MIRD) Committee formalism. The tumor growth rate in mice injected with a single intraperitoneal administration of 300 microCi of 131I-labeled MoAb was reduced relative to tumor growth in untreated control animals and in mice administered unlabeled MoAb and was found to be similar to the growth rate of tumors given a single 6 Gy dose of 60Co radiation. Furthermore, the growth rate of tumors in mice that received three injections of 300 microCi of 131I-labeled MoAb on days 9, 16 and 28 after tumor cell injection was similar to the growth rate of tumors given a single 60Co dose of 8 or 10 Gy. The biodistribution data for 125I-labeled 17-1A MoAb were used to calculate total doses for the tumor and various normal tissues in animals given a single administration of 131I-labeled 17-1A MoAb. The absorbed radiation dose in tumor was approximately five times higher than in normal tissues. The results of the present study indicate that the tumor growth inhibition produced by the administration of radiolabeled antibody can equal that produced by up to 10 Gy of external beam radiation. In addition, the MIRD calculations allow comparison of this form of low dose radiation to external photon irradiation.

Animals↗
PubMed1990

Doxorubicin decreases the repair of radiation-induced DNA damage.

The mechanism that underlies doxorubicin-induced radiosensitization was investigated in a cell culture system. When V79 hamster cells were treated with doxorubicin, radiosensitization occurred as illustrated by an increase in alpha and a reduction in the mean inactivation dose (D) of the radiation survival curve. Under control conditions the radiation survival curve showed an alpha of 0.010 +/- 0.02 and a D of 4.4 +/- 0.2. After exposure to doxorubicin (1.5 micrograms/ml for 1 h prior to irradiation), alpha increased to 0.28 +/- 0.04 and D decreased to 3.0 +/- 0.3. Similar mean inactivation doses were found for doxorubicin doses of 0.75, 1.5 and 3.0 micrograms/ml, indicating that enhancement was not dose-dependent in the dose range studied. The influence of doxorubicin on radiation-induced DNA double-strand breaks (dsb) was then assessed under the same conditions as were used in the cell survival studies. Pretreatment with doxorubicin minimally affected radiation-induced dsb. However, doxorubicin increased dsb by 1.25 +/- 0.07 under conditions in which repair was allowed to proceed for 45 min. These results show that doxorubicin inhibits the repair of radiation-induced dsb. Doxorubicin is known to change DNA conformation by the stabilization of DNA topoisomerase II complexes. It is possible that these changes alter the ability of repair enzymes to recognize and correct radiation-induced damage.

Animals↗
PubMed1990

Common deficiencies of NIDRR research applications.

The purpose of this article was to identify and describe those deficiencies determined by nonfederal peer reviewers during the most recent 1989 NIDRR research competition to mitigate successful funding support from the lead federal agency concerned with medical rehabilitation research. In 1989, 232 field investigator-initiated research applications were received in response to the Federal Register announcement of September 8, 1988. Of these, 57 or 24.5% were assigned to the Medical Sciences Programs office. Six applications were ultimately approved and funded (10.7%). The remaining 51 (89.5%) were statistically analyzed to determine deficiencies significant in warranting disapproval. The 51 applications averaged 5.68 deficiencies each. Five types of research error accounted for 76.8% of all deficiencies noted by reviewers. These included methodologic errors (25) and inadequate control of subject variables (25), followed by inappropriate research design (24), poor conceptualization of problem/approach (21) and incorrect statistical analysis (14). The top ranked singular deficiency was poor conceptualization of problems or approach. Other flaws warranting lowering of potential scores by reviewers included excessive budget requests, duplication of effort with on-going supported research, inadequate background of investigator and weak dissemination and utilization plans. In conclusion, many applications are submitted for the NIDRR field investigator-initiated research program competitions that are significantly deficient. Those identified areas of deficiency cover most oF the conceptualization, research design and methodologic criteria essential for valid, creditable scientific investigation.(ABSTRACT TRUNCATED AT 250 WORDS)

Government Agencies↗
PubMed1990

New trends in the use of radioimmunoconjugates for the therapy of cancer.

Since 1980, there has been intense research in the area of radiolabeled immunoconjugates for the localization and therapy of cancer in both experimental animal models and in humans. This is based on the potential of MoAbs reactive with tumor-associated antigens as specific carriers of radionuclides, toxins, and chemotherapeutic drugs. Even though there has been much progress, a great deal of work and innovation will be required before the use of radiolabeled immunoconjugates becomes an established method for clinical tumor detection and therapy. The greatest problem is the relatively low tumor uptake of radiolabeled MoAbs in humans. This results in relatively high background levels of radioactivity in normal tissues and insufficient radioactivity in the tumor for the detection of small lesions and for therapeutic efficacy. In the future, one can expect the development of new MoAbs with greater specificity for particular tumor types, improvements in radiolabeling procedures, and the use of more effective nuclides than 131I. Biological, physiological, pathological, and dosimetric considerations need to be addressed in detail. With this additional information, it is hoped that the full potential for radiolabeled immunoconjugates will be realized.

Animals↗
PubMed1990

The effect of single versus double-strand substitution on halogenated pyrimidine-induced radiosensitization and DNA strand breakage in human tumor cells.

To better understand the mechanism underlying halogenated pyrimidine-mediated cytotoxicity and radiosensitization in human tumor cells, a study was undertaken to determine the influence of unifilar (one DNA strand) versus bifilar (both DNA strands) substitution of thymidine by the halogenated bases 5-iodo-2'-deoxyuridine (IdUrd) and 5-bromo-2'-deoxyuridine (BrdUrd) in HT29 human colon cancer cells. Unifilar labeling was obtained by incubating cells with IdUrd or BrdUrd for one doubling time. Cells were incubated for at least three doublings to approximate bifilar substitution. Only IdUrd caused significant cytotoxicity, which correlated with incorporation into DNA. Both BrdUrd and IdUrd were potent radiosensitizers. Radiosensitization was linearly correlated with incorporation of both bases regardless of the number of strands in which thymidine was substituted. In contrast, the relationship between radiosensitization and DNA double-strand breakage was critically dependent in the case of IdUrd, but not for BrdUrd, on whether substitution was unifilar or bifilar. These findings suggest that incorporation is the best predictor of radiation sensitivity, and that the induction of DNA double-strand breaks alone does not account for radiosensitization mediated by halogenated pyrimidines in these human tumor cells.

Bromodeoxyuridine↗
PubMed1989

Dependence of etoposide-induced cytotoxicity and topoisomerase II-mediated DNA strand breakage on the intracellular ionic environment.

We have found that blockade of the Na+,K+-pump by the cardiac glycoside ouabain protects human A549 and hamster V79 cells from the cytotoxic effects of the topoisomerase II poison etoposide. One thousand-fold higher concentrations of ouabain were required to protect V79 cells compared to A549 cells. Since this difference parallels previously measured differences in pump sensitivity, it suggests that protection is mediated directly through pump blockade. Ouabain affected neither the cellular influx nor efflux of etoposide. However, pump blockade did decrease the formation of etoposide-induced DNA-topoisomerase, II-cleavable complexes, assessed as single and double strand DNA breaks using alkaline and neutral elution. To determine if this decrease were a direct effect of change in ionic environment produced by pump blockade, experiments with isolated nuclei and partially purified topoisomerase II were performed. Etoposide-induced cleavable complex formation and topoisomerase-mediated decatenation were assessed in buffers which mimicked either normal intracellular ionic conditions or those produced by ouabain. Compared to the buffer which resembled the normal intracellular ionic conditions, the buffer that mimicked the conditions produced by pump blockade produced fewer etoposide-mediated cleavable complexes in isolated nuclei and less decatenating activity of partially purified topoisomerase II. These findings demonstrate that inhibition of the Na+,K+-pump causes an alteration in the intracellular ionic environment which decreases the activity of topoisomerase II, thus producing a decrease in etoposide-induced cleavable complex formation and cytotoxicity. Since ionic changes occur inside normal cells during progression through the cell cycle as well as in cells that have undergone transformation, these data suggest that the intracellular ionic environment plays a role in determining the sensitivity of normal and malignant cells to this group of chemotherapeutic agents.

Animals↗
PubMed1989

Protection of doxorubicin cytotoxicity by cycloheximide.

The effect of cycloheximide (an inhibitor of cellular protein synthesis) on doxorubicin-induced cytotoxicity in V79 (rodent fibroblasts) cells was investigated. Cycloheximide is a potent protector of doxorubicin-induced cytotoxicity at concentrations paralleling those required for protein synthesis inhibition. The greatest protective effect was achieved at 10 microM cycloheximide; this concentration correlated with 95% inhibition of protein synthesis. A 15 minute cycloheximide (10 microM) exposure resulted in maximal protein synthesis inhibition; however, 4-6 hr of pretreatment with cycloheximide (10 microM) was required to maximally protect cells from doxorubicin. These results suggest that a time-dependent depletion of a protein is required for cycloheximide's protective effect. Cycloheximide treatments were found to decrease intracellular accumulation of doxorubicin by 35-50% but this decrease accounts for only a small fraction of the total protective effect. When corrections were made for differences in doxorubicin accumulation, cycloheximide had no effect on the formation of DNA-protein crosslinks (DNA-topoisomerase II complexes revealed as single strand DNA breaks in alkaline elution studies). These studies suggest that cycloheximide confers protection from doxorubicin cytotoxicity by a step which occurs following the stabilization of DNA-topoisomerase II complexes.

Animals↗
PubMed1989

Selective radiosensitization and cytotoxicity of human melanoma cells using halogenated deoxycytidines and tetrahydrouridine.

The halogenated pyrimidines 5-chloro-2'-deoxycytidine (CldCyd) and 5-bromo-2'-deoxycytidine (BrdCyd) can act as radiosensitizers and cytotoxic agents. It was hypothesized that tumor cells and normal cells might use different metabolic pathways to incorporate these halogenated deoxycytidines into DNA. This difference could potentially be exploited to produce selective radiosensitization and cytotoxicity of human tumor cells compared to normal human fibroblasts. This hypothesis was tested using two human melanoma cell lines and two normal fibroblast cell lines. Either CldCyd or BrdCyd alone caused both cytotoxicity and radiosensitization of tumor and normal cells. The addition of the cytidine deaminase inhibitor tetrahydrouridine (H4U) significantly protected the normal cells but had relatively little effect on the tumor cells. These data indicate that it may be possible to exploit differences between the pyrimidine metabolism of normal cells and melanoma cells to improve the therapeutic index of halogenated pyrimidines both as radiosensitizers and as cytotoxic agents.

Antineoplastic Agents↗
PubMed1988

Reduction of doxorubicin cytotoxicity by ouabain: correlation with topoisomerase-induced DNA strand breakage in human and hamster cells.

The cardiac glycoside ouabain, which is a specific inhibitor of the Na+,K+-pump, confers dramatic protection from the cytotoxic effects of doxorubicin (Adriamycin). This effect was documented in cultured A549 cells (human lung adenocarcinoma). CCL210 cells (human fibroblasts), and V79 cells (hamster fibroblasts). Maximum protection from doxorubicin cytotoxicity was achieved using 1 microM ouabain for A549 and CCL210 cells and 300 microM ouabain for V79 cells. These concentrations correlated well with the concentrations of ouabain required to induce Na+,K+-pump blockade, which was assessed using the K+ analogue 86Rb+. This suggests that protection is mediated by pump blockade. Addition of ouabain at the same time as doxorubicin was just as protective as preincubation with ouabain for an hour, demonstrating that the ouabain acts rapidly. Ouabain treatment affected neither influx nor efflux of doxorubicin. Ouabain also had no effect on verapamil-induced inhibition of doxorubicin efflux. However, ouabain partially blocked the verapamil-induced potentiation of the cytotoxic effects of doxorubicin. Therefore, ouabain does not protect by affecting intracellular doxorubicin levels. Fluorescence microscopy showed that the ability of doxorubicin to reach the nucleus was not influenced by ouabain. Alkaline elution studies demonstrated that ouabain greatly decreased doxorubicin-induced DNA strand breakage. Protection from cytotoxicity correlated closely with this decrease in strand breakage. These studies suggest that the stabilization of DNA-topoisomerase II complexes is closely linked to the mechanism of doxorubicin cytotoxicity and that this stabilization is influenced by the intracellular ionic milieu.

Animals↗
PubMed1988

Ouabain sensitizes tumor cells but not normal cells to radiation.

Ouabain is a cardiac glycoside that blocks the sodium, potassium-pump (Na,K-Pump). When A549 human lung adenocarcinoma cells were treated with 10(-6) M ouabain for 4 hr starting 1 hr before irradiation, they were sensitized (enhancement ratio at 1% survival 1.46 +/- .07, N = 5). Ouabain affected radiation repair because it decreased the shoulder of the cell survival curve and it sensitized cells when added after radiation. CCL-210 normal human lung fibroblasts were not radiosensitized by ouabain concentrations from 10(-8) M to 10(-5) M. These results suggest that it may be possible to exploit differences in the Na,K-pumps of normal cells and tumor cells to improve the therapeutic index of radiation.

Adenocarcinoma↗
PubMed1988

Retrospective analysis of stage I and II indolent lymphomas at the National Cancer Institute.

We have retrospectively reviewed the records of 54 patients with Stages I and II indolent lymphoma treated at the National Cancer Institute between January 1958 and December 1984. Patients were treated by a variety of approaches, with 48/54 patients receiving some form of radiation therapy. The median potential follow-up was 9 years (rang 1.7-23.7 years). Overall survival and disease-free survival at 10 years were 69% and 48%, respectively. There were no relapses among Stage I patients after 6.5 years, with 11 of 27 patients followed beyond that time, suggesting that some patients may be cured. Of the 38 patients who received radiation therapy alone as primary treatment, 17 ultimately relapsed. Seventy-one percent of these relapses were nodal. Our data suggest that patients with early stage indolent lymphoma can be treated with curative intent. The finding that most relapses after radiation therapy occur in untreated lymph nodes suggests that total lymphoid irradiation may prolong disease-free survival and, perhaps, overall survival as well.

Adolescent↗
PubMed1985

Retinal toxicity after high-dose cisplatin therapy.

Because of increasing complaints of visual dysfunction, 13 patients with refractory or recently diagnosed ovarian carcinoma were evaluated for possible cisplatin-induced ophthalmologic toxicity. All patients had received high-dose cisplatin (200 mg/m2 in five divided daily doses) over two to four cycles. Eight patients (62%) developed symptoms of blurred vision and three (23%) also developed altered color perception. Retinal toxicity in the form of cone dysfunction was documented by electroretinography and color vision testing in 11 patients. Three patients were studied prospectively. Two patients who developed cone dysfunction had normal ophthalmologic exams before the initiation of chemotherapy or after one cycle of cisplatin, suggesting a causal relationship between cisplatin therapy and subsequent retinal abnormalities. Though visual acuity improved off therapy, color vision abnormalities persisted as long as 16 months beyond therapy.

Adult↗
PubMed1980

Binding of human chorionic gonadotropin by rat cumuli oophori and granulosa cells: a comparative study.

Cumulus oocyte complexes isolated from PMS gonadotropin-primed immature rats bind [125I]hCG. Unlabeled hCG and ovine LH compete with the labeled hormone for binding sites, while rat FSH and ovine PRL are without effect. Since specific binding of [125I]hCG could not be detected in preparations of oocytes from which the cumuli had been removed, it appears that the binding exhibited by the complex can be attributed to the cumulus cells. The concentration dependence of binding is consistent with the presence of one population of high affinity (apparent Kd, 1.4 X 10(-10) M) binding sites (223 +/- 33 sites/cumulus cell). Rat granulosa cells bind hCG with equivalent apparent affinity and specificity but contain more sites (2060 +/- 180/cell) than cumulus cells.

Animals↗
PubMed1979

Hormonally induced cell shape changes in cultured rat ovarian granulosa cells.

Cultured rat ovarian granulosa cells undergo a dramatic morphological change when exposed to follicle-stimulating hormone (FSH). Exposure to FSH causes the flattened epithelioid granulosa cells to assume a nearly spherical shape while retaining cytoplasmic processes which contact the substrate as well as adjacent cells. This effect of FSH is preceded by a dose-dependent increase in intracellular cAMP, is potentiated by cyclic nucleotide phosphodiesterase inhibitors, and is mimicked by dibutyryl cAMP. Prostaglandins E1 or E2 and cholera enterotoxin also cause the cells to change shape. A subpopulation of the cells responds to luteinizing hormone. These morphological changes, which are blocked by 2,4-dinitrophenol, resemble those produced by treating cultures with cytochalasin B. Electron microscopy shows that the unstimulated, flattened cells contain bundles of microfilaments particularly in the cortical and basal regions. After FSH stimulation, microfilament bundles are not found in the rounded granulosa cell bodies but they are present in the thin cytoplasmic processes. These data suggest that the morphological change results from a cAMP-mediated, energy-dependent mechanism that may involve the alteration of microfilaments in these cells.

Animals↗
PubMed1978

Transmission of hormonal stimulation by cell-to-cell communication.

Rat ovarian granulosa cells and mouse myocardial cells respond to cell-specific hormones by cyclic AMP-dependent mechanisms. In coculture, these heterologous cells communicate by means of gap junctions. Exposure of the cocultures to a hormone specific for one cell type causes the heterologous cells to respond through a cell contact-dependent mechanism. These studies suggest that this cross-stimulation results from the intercellular communication of a mediator that is common to both cell types. The communicated mediator may be cyclic AMP.

Cell Communication↗