Biomedical subjects

J E Moulder

Publications and source records attributed to J E Moulder.

At least 73 records · Page 4Linked to original sources

PubMed1991

Late renal dysfunction in adult survivors of bone marrow transplantation.

Until recently long-term renal toxicity has not been considered a major late complication of bone marrow transplantation (BMT). Late renal dysfunction has been described in a pediatric population status post-BMT which was attributable to the radiation in the preparatory regimen. A thorough review of adults with this type of late renal dysfunction has not previously been described. Fourteen of 103 evaluable adult patients undergoing allogeneic (96) or autologous (7) bone marrow transplantation, predominantly for leukemia and lymphomas, at the Medical College of Wisconsin (Milwaukee, WI) have had a syndrome of renal insufficiency characterized by increased serum creatinine, decreased glomerular filtration rate, anemia, and hypertension. This syndrome developed at a median of 9 months (range, 4.5 to 26 months) posttransplantation in the absence of specific identifiable causes. The cumulative probability of having this renal dysfunction is 20% at 1 year. Renal biopsies performed on seven of these cases showed the endothelium widely separated from the basement membrane, extreme thickening of the glomerular basement membrane, and microthrombi. Previous chemotherapy, antibiotics, and antifungals as well as cyclosporin may add to and possibly potentiate a primary chemoradiation marrow transplant renal injury, but this clinical syndrome is most analogous to clinical and experimental models of radiation nephritis. This late marrow transplant-associated nephritis should be recognized as a potentially limiting factor in the use of some intensive chemoradiation conditioning regimens used for BMT. Some selective attenuation of the radiation to the kidneys may decrease the incidence of this renal dysfunction.

Adolescent↗

PubMed1991

Radiation induction of drug resistance in RIF-1: correlation of tumor and cell culture results.

The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual. We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors.

Animals↗

PubMed1991

Influence of nephrotoxic drugs on the late renal toxicity associated with bone marrow transplant conditioning regimens.

The total body irradiation that is given as part of bone marrow transplant conditioning regimens is a factor in the renal toxicity that is observed after bone marrow transplant, but it may not be the only factor. We hypothesize that nephrotoxic drugs used in prior chemotherapy can precipitate renal radiation damage. Studies were designed to determine if nephrotoxic antineoplastic drugs could shorten the latent period for the development of radiation nephritis. Rats were given bilateral renal irradiation using a radiation schedule that produced moderate nephritis. Cisplatinum, BCNU, or mitomycin were given before, during, or after irradiation at doses that produced only mild nephrotoxicity. All cisplatinum-radiation sequences resulted in decreased renal function, with radiation prior to cisplatinum producing the greatest dysfunction. BCNU increased renal dysfunction equally in all schedules, but mitomycin had only minimal effects. Most drug schedules, including those with mitomycin, produced earlier development of morbidity after fractionated renal irradiation. In a second set of studies, rats were given single doses of the same nephrotoxic drugs, followed 3 months later by total body irradiation plus bone marrow transplant. The drugs had no effect on the marrow ablation dose, but BCNU and cisplatinum decreased gastrointestinal tolerance. Four months after total body irradiation, rats which received drugs alone or total body irradiation alone have essentially normal renal function, but rats which received cisplatinum plus total body irradiation or BCNU plus total body irradiation show a dose-dependent decrease in renal function. These studies show that radiation nephritis can be precipitated by low doses of nephrotoxic drugs, and may help to explain the incidence of early radiation nephritis in bone marrow transplant patients conditioned with total body irradiation.

Animals↗

PubMed1991

Prediction of tumor radiosensitivity by hexafluoromisonidazole retention monitored by [1H]/[19F] magnetic resonance spectroscopy.

Hexafluoromisonidazole (CCI-103F) is a hypoxic cell label that can be measured by in vivo [1H]/[19F] magnetic resonance spectroscopy (MRS). The retention of CCI-103F in SCCVII tumors was found to be correlated with tumor size, with larger tumors retaining more label. Such a correlation was anticipated, as larger SCCVII tumors have larger hypoxic fractions. A significant but less strong correlation was also found between CCI-103F retention and the fraction of tumor cells surviving after 10 Gy irradiation, with tumors that retained larger amounts of CCI-103F having higher surviving fractions. These results indicated that non-invasive MRS measurement of CCI-103F retention could predict radiosensitivity in SCCVII tumors. The lack of a strong correlation between CCI-103F retention and radiosensitivity, however, indicated that hypoxic fraction was not the only factor influencing radiosensitivity in these tumors.

Animals↗

PubMed1990

Hypoxic fractions of human tumors xenografted into mice: a review.

Transplanted tumors in rats and mice have been used extensively in radiobiology studies examining the biological basis and therapeutic implications of hypoxia in solid tumors, and in studies evaluating new agents and regimens which may circumvent the radioprotective effects of hypoxic cells. This use of rodent tumors assumes that data obtained using rapidly-growing transplanted tumors arising in inbred rodents can be extrapolated meaningfully to the treatment of primary and/or metastatic lesions in heterozygous humans. The studies reported here examine one facet of this critical assumption by comparing the hypoxic fractions of transplanted rodent tumors with those of human tumor cell lines xenografted into immune deficient mice. No significant differences were found between the hypoxic fractions of the xenografts and those of mouse tumors. This finding eliminates several possible bases for predicting that the oxygenation of human tumors might be systematically different from that of the rodent tumors often used in preclinical radiobiology studies, and supports the hypothesis that human tumors contain hypoxic cells which may be critical in determining their response to therapy.

Animals↗

PubMed1990

Hepatic function and drug pharmacokinetics after total body irradiation plus bone marrow transplant.

Radiation nephritis is the principle late toxicity seen after total body irradiation in barrier-maintained rats when hematologic toxicity is prevented by bone marrow transplantation. Renal dysfunction is observed for single doses as low as 7.5 Gy. Hepatic blood flow, as measured by indocyanine green clearance, is decreased after 8.5-9.5 Gy single-dose total body irradiation. Serum albumin levels are decreased after 9.5 Gy single-dose total body irradiation. Hypoalbuminemia is a symptom of hepatic damage, but can also be caused by renal damage or edema. No decrease in total serum protein is observed, indicating that proteinuria resulting from renal damage is not the cause of hypoalbuminemia. No edema and some dehydration are observed. These data indicate that hepatic damage as well as renal damage may be occurring after total body irradiation plus bone marrow transplantation. Animals given total body irradiation plus bone marrow transplantation show decreased tolerance to a wide variety of immunosuppressive and cytotoxic drugs, even when these drugs are given months after total body irradiation. Altered drug clearance after total body irradiation plus bone marrow transplantation is observed for cis-platinum, vincristine, and adriamycin. The increase in cis-platinum toxicity after total body irradiation plus bone marrow transplantation is caused by decreased renal drug clearance. The decrease in vincristine tolerance and the alterations in adriamycin and vincristine pharmacokinetics are caused by altered drug distribution after total body irradiation plus bone marrow transplantation. These results indicate that bone marrow transplant survivors may show altered clearance of, and decreased tolerance to, a wide variety of drugs that are used after bone marrow transplantation.

Animals↗

PubMed1990

Drug resistance following irradiation of RIF-1 tumors: influence of the interval between irradiation and drug treatment.

RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance.

Animals↗

PubMed1990

Tumor and normal tissue tolerance for fractionated low-dose-rate radiotherapy.

Radiobiological evidence suggests that an improved therapeutic ratio might be achieved through the use of smaller than conventional dose fractions. The ultimate in small dose fractions for external beam radiotherapy would be fractionated low-dose-rate (LDR) irradiation, and clinical trials of fractionated external beam LDR therapy are already in progress. Using the BA1112 rat sarcoma, we have determined the 50% tumor control dose for LDR and for conventional-dose-rate (CDR) fractionated radiotherapy. These tumor control doses were compared to normal tissue tolerance doses for hemi-body irradiation in similar CDR and LDR schedules. Animals were treated 3 times per week without anesthesia using 10-19 fractions. LDR radiotherapy was done with 60Co at dose rates of 0.028-0.033 Gy/min; CDR radiotherapy was done with 250 kVp X rays at dose rates of 0.54-2.1 Gy/min. The tumor control dose modification factor (DMF) for LDR compared to CDR irradiation was 1.3 (1.0-1.5). For LDR and CDR hemi-body irradiation, the dose modification factor for 7 day lethality (gastrointestinal damage) was 1.7 (1.5-1.9), for 100 day morbidity was 1.8 (1.6-2.2), and for radiation nephritis at 90 days was 1.9 (1.7-2.3). The therapeutic gain factor for fractionated low-dose-rate irradiation compared to conventional-dose-rate fractionated radiotherapy was therefore 1.8/1.3 = 1.4 (1.2-1.8). The study shows that there is an experimental as well as a theoretical basis for anticipating a therapeutic benefit from the use of external beam fractionated LDR radiotherapy, and implies that the recognized therapeutic efficacy of brachytherapy is not due solely to the high localized dose.

Animals↗

PubMed1990

Dynamic measurements of hexafluoromisonidazole (CCI-103F) retention in mouse tumours by 1H/19F magnetic resonance spectroscopy.

Selective retention of hexafluoromisonidazole, CCI-103F, in RIF-1 and SCCVII tumours of C3H/Km mice has been measured by 1H/19F magnetic resonance spectroscopy (MRS) on a Bruker AM-400 multinuclear spectrometer. CCI-103F concentrations in tumours and in normal tissues were measured using an MRS technique in which the water component in the tissues serves as an internal concentration reference. The biodistribution and elimination half-life of the drug in the tissues after i.p. injections were determined. The plasma half-life of the drug (41 min) was measured by high-pressure liquid chromatography. The two tumour lines and liver have longer retention times with half-lives of 47, 129 and 81 min, respectively, while normal tissues, muscle and brain have little retention of CCI-103F and clear the drug very quickly. Dynamic measurements of CCI-103F retention in tumours by MRS may provide a non-invasive probe for assessing tumour hypoxia.

Animals↗

PubMed1989

Late toxicity of total body irradiation with bone marrow transplantation in a rat model.

In defined-flora, barrier-maintained rats, radiation nephritis is the principle late toxicity seen after high dose-rate total body irradiation (TBI), when hematologic toxicity is prevented by bone marrow transplantation (BMT). Pneumonitis develops only if rats are placed in a conventional microbiological environment during and after BMT. Low dose-rate TBI gives qualitatively similar late toxicity, but at radiation doses twice as large. Fractionation of the TBI has little effect on the bone marrow ablation doses, but results in increased gastrointestinal and renal tolerance. The addition of immunosuppressive or cytotoxic drugs (cyclosporine-A, methotrexate, cis-platinum) after TBI and BMT greatly decreases the dose of TBI that can be tolerated. The use of a cyclophosphamide plus cytosine arabinoside conditioning regimen prior to TBI and BMT increases the bone marrow ablation dose, but has no effect on acute gastrointestinal toxicity or on renal toxicity. These results indicate that substantial late toxicity may be associated with the TBI conditioning regimens used for BMT even in the absence of cytotoxic and antibiotic drugs, immunosuppressive agents, infection and graft-versus-host disease; and that radiation may be a contributing factor in the nephritis sometimes observed after TBI and BMT.

Animals↗

PubMed1989

Radiation induction of drug resistance in RIF-1 tumors and tumor cells.

The RIF-1 tumor cell line contains a small number of cells (1-20 per 10(6) cells) that are resistant to various single antineoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), and adriamycin (ADR). For 5FU the frequency of drug resistance is lower for tumor-derived cells than for cells from cell culture; for MTX the reverse is true, and for ADR there is no difference. In vitro irradiation at 5 Gy significantly increased the frequency of drug-resistant cells for 5FU, MTX, and ADR. In vivo irradiation at 3 Gy significantly increased the frequency of drug-resistant cells for 5FU and MTX, but not for ADR. The absolute risk for in vitro induction of MTX, 5FU, and ADR resistance, and for in vivo induction of 5FU resistance, was 1-3 per 10(6) cells per Gy; but the absolute risk for in vivo induction of MTX resistance was 54 per 10(6) cells per Gy. The frequency of drug-resistant cells among individual untreated tumors was highly variable; among individual irradiated tumors the frequency of drug-resistant cells was significantly less variable. These studies provide supporting data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be due to radiation-induced drug resistance.

Animals↗

PubMed1988

Effects of fractionated doses of ionizing radiation on small intestinal motor activity.

The small intestinal motor effects of fractionated doses of ionizing radiation were studied in 6 conscious dogs. Eight strain-gauge transducers were implanted on the small intestine and a single gauge on the ascending colon, of each dog. After control recordings, an abdominal dose of 250 cGy was administered three times a week on alternate days for 3 successive weeks (total dose, 2250 cGy). Recordings were then made for 4 wk of follow-up. Giant migrating contractions occurred 11 times in 520 h of control recordings in the fasted and fed state, with a mean distance of origin of 55 +/- 16 cm from the ileocolonic junction. Abdominal field irradiation significantly increased the incidence and distance of origin of these giant contractions to 438 in 745 recording hours and 158 +/- 7 cm from the ileocolonic junction, respectively. The incidence of giant migrating contractions peaked after the second dose of radiation. The amplitude ratio of radiation-induced giant migrating contractions to phase III contractions, and their duration and velocity of migration, were similar to the control state. The dogs developed diarrhea and vomiting as early as the first fraction of radiation. Irradiation also increased the incidence of retrograde giant contractions from 8 in 520 h of control recording to 42 in 745 h of recording during the radiation schedule. The radiation-induced retrograde giant contractions peaked in incidence on the day of the first fraction of radiation and were more likely to be associated with a vomiting episode than those occurring in the control period. Migrating motor complex cycling persisted during radiation and its cycle length was not different from the control or postradiation values. Our findings suggest that some of the side effects of radiation such as diarrhea, abdominal cramping, and vomiting may be related to the dramatically increased incidence of giant migrating contractions and retrograde giant contractions.

Animals↗

PubMed1988

Applicability of animal tumor data to cancer therapy in humans.

The problem of applying experimental tumor studies to clinical cancer therapy is a complex one. The radiotherapy literature contains many examples of premature efforts to apply laboratory observations to the clinic, and many examples of failures to adequately consider animal tumor observations in the design of clinical studies. This review covers three areas: tumor hypoxia, where clinical trials based on animal tumor data have been conducted with radiosensitizers, hyperbaric oxygen, and systemic oxygen carriers; dose fractionation, where current trials of hyperfractionation are based in part on animal tumor studies; and chemo-radiotherapy, where clinical trials are only beginning to exploit concepts developed in animal tumor systems. The use of animal tumor systems extends past the screening of new agents. Animal tumor models can be used in biological, physiological, and pharmacological studies to elucidate the biological factors influencing the efficacy of therapeutic agents. Tumor studies can be combined with studies of normal tissues to predict the toxicities to be anticipated in clinical trials, and to assess the potential for therapeutic gain. Animal studies can also provide data which are useful in designing optimal clinical trials of new agents and maximizing the potential for successful clinical application of new approaches. In general, it is not possible to apply specific laboratory data directly to man. To translate, rather than transpose, information from the laboratory to the clinic, the model studies must be directed at evaluating principles, rather than merely quantifying results. Only through studies of mechanisms, by designing experiments to test or refute a hypothesis, will it be possible to apply model studies to man.

Animals↗

PubMed1988

Intermittent use of a perfluorochemical emulsion (Fluosol-DA 20%) and carbogen breathing with fractionated irradiation.

Oxygen carrying perfluorochemical emulsions have been shown to enhance the response of animal tumors to large single doses of radiation. Clinically, however, perfluorochemical emulsions are being used with only some fractions in multiple fraction radiation courses. To test the efficacy of a perfluorochemical emulsion under conditions that are closer to those used in current clinical trials, BA1112 rat sarcomas were treated with three fractions per week of 6 Gy per fraction. Once a week, animals were infused i.v. with a perfluorochemical emulsion at 15 ml/kg, and allowed to breathe carbogen (95% O2:5% CO2) for 30 minutes prior to and during irradiation. The 50% tumor control dose was 93.1 (87.9-103.1) Gy in the control arm compared to 74.3 (64.9-83.9) Gy for the animals given the perfluorochemical infusion plus carbogen breathing. The dose modification factor for intermittent perfluorochemical infusion and carbogen breathing was 1.26 (1.15-1.40). In a similar fractionated schedule, the hypoxic cell radiosensitizer, misonidazole, given once per week at 600 mg/kg, gave a dose modification factor of 1.22 (1.14-1.32).

Administration, Inhalation↗

PubMed1988

Effect of total-body irradiation with bone marrow transplantation on toxicity of cisplatin.

In defined-flora, barrier-maintained rats (WAG/RijMCW males), radiation nephritis is the principal late toxicity seen after high-dose-rate, total-body irradiation (TBI) when hematologic toxicity is prevented by bone marrow transplantation. Pneumonitis develops only if rats are exposed to a conventional environment during and after bone marrow transplantation. Low-dose-rate TBI gives similar toxicity at doses twice as large. Rats surviving for 9 months after TBI show decreased tolerance for cisplatin. This decreased tolerance is related to dose and dose rate and is seen for radiation doses that show little or no renal toxicity. Evidence suggests that the decrease in renal tolerance is due to decreased renal platinum clearance in the irradiated kidneys.

Animals↗

PubMed1988

Effect of sequencing on combined toxicity of renal irradiation and cisplatin.

We are using a rat model to study the effects of sequencing on the combined toxicity of renal irradiation and cisplatin (cis-Pt). Unanesthetized female WAG/RijMCW rats were given bilateral kidney irradiation (20 Gy in 9 fractions), preceded or followed by single ip doses of cis-Pt. Renal irradiation causes an increase in the acute toxicity of cis-Pt given 3-9 months after irradiation. Low-dose cis-Pt given immediately before irradiation, or as long as 9 months after irradiation, causes a decrease in the latent period for radiation nephritis and an increase in its severity. When given 3.7 to 7.7 months prior to irradiation, cis-Pt has a less severe effect on radiation nephritis. The greatest enhancement of radiation nephritis is seen for cis-Pt given 3 months after irradiation. Additive effects of cis-Pt and radiation on renal function can explain much, but not all, of the combined toxicity.

Animals↗

PubMed1987

Tumor hypoxia: its impact on cancer therapy.

The presence of radiation resistant cells in solid human tumors is believed to be a major reason why radiotherapy fails to eradicate some such neoplasms. The presence of unperfused regions containing hypoxic cells may also contribute to resistance to some chemotherapeutic agents. This paper reviews the evidence that radiation resistant hypoxic cells exist in solid tumors, the assumptions and results of the methods used to detect hypoxic cells, and the causes and nature of tumor hypoxia. Evidence that radiation resistant hypoxic cells exist in the vast majority of transplanted rodent tumors and xenografted human tumors is direct and convincing, but problems with the current methodology make quantitative statements about the magnitude of the hypoxic fractions problematic. Evidence that radiation resistant hypoxic cells exist in human tumors is considerably more indirect than the evidence for their existence in transplanted tumors, but it is convincing. However, evidence that hypoxic cells are a significant cause of local failure after optimal clinical radiotherapy or chemotherapy regimens is limited and less definitive. The nature and causes of tumor hypoxia are not definitively known. In particular, it is not certain whether hypoxia is a chronic or a transient state, whether hypoxic cells are proliferating or quiescent, or whether hypoxic cells have the same repair capacity as aerobic cells. A number of new methods for assessing hypoxia are reviewed. While there are still problems with all of the new techniques, some of them have the potential of allowing the assessment of hypoxia in individual human tumors.

Animals↗

PubMed1987

Chronic effects of fractionated renal irradiation on the pharmacokinetics of intravenous methotrexate.

the chronic effects of renal irradiation on the pharmacology of methotrexate was studied in a rat model. Unanesthetized rats received 2 doses of bilateral fractionated kidney irradiation (16.2 Gy or 19.8 Gy in 9 fractions). Alterations in renal function were first seen at 3 months in the 19.8 Gy group and 12 months in the 16.2 Gy groups. Life table analysis showed a shift in the survival curve of about 3 months between the 2 radiation doses. The pharmacokinetics of i.v. methotrexate showed an increase in the area under the plasma curve beginning at 9 months in the 19.8 Gy group and at 15 months in the 16.2 Gy group. The volume of distribution of methotrexate was smaller in the irradiated rats than in unirradiated controls. Multiple linear regression models showed significant correlations between parameters of methotrexate clearance and certain renal function tests. Nevertheless, no set of renal function tests consistently predicted alteration in methotrexate clearance in the 2 radiation groups. Furthermore, time after irradiation remained a highly significant variable indicating that renal irradiation causes time dependent change in methotrexate pharmacokinetics that can not be accounted for by the usual tests of renal function.

Animals↗