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B F Kimler

Publications and source records attributed to B F Kimler.

At least 73 records · Page 4Linked to original sources
PubMed1988

Potentiation of rat brain tumor therapy by fluosol and carbogen.

We have been using the 9L rat brain tumor model to investigate the effect of the combination of a perfluorochemical emulsion, Fluosol-DA 20%, and carbogen breathing on the therapy of brain tumors. The combination of Fluosol, carbogen breathing, and carmustine (BCNU) was more effective at prolonging survival than was BCNU alone. This difference was small but significant (P less than 0.25). neither Fluosol without carbogen nor carbogen without Fluosol significantly altered the effect of BCNU. Fluosol and carbogen alone did not affect the survival of tumor-burdened rats. Fluosol and carbogen breathing did not alter the effect of single doses of radiation on these tumors. This result supports the hypothesis that 9L brain tumors contain few, if any, critical hypoxic cells. However, these tumors may contain cells which are oxygen deficient but not radiobiologically hypoxic. The Fluosol-carbogen combination may be changing the intratumor environment in such a way that the metabolism or activity of BCNU is altered.

Animals↗
PubMed1988

Total lymphoid irradiation retards evolution of articular erosions in collagen induced arthritis.

Collagen induced arthritis was elicited in rats and monitored with serial magnification radiographs and serologic studies. Total lymphoid irradiation (TLI), 1050 rad in 3 fractions, was given at 1 of 2 days after primary immunization. Erosive arthritis and periostitis evolved more slowly in rats irradiated on Day 9 compared to nonirradiated control animals; in contrast, rats irradiated on Day 21 showed no significant differences. At Day 114 neither group receiving TLI differed from nonirradiated controls. Additional groups of rats were irradiated at varying times relative to collagen immunization. On Day 18 the mean IgM and IgG anticollagen antibody responses were transiently decreased in animals receiving TLI by Day 9, with no differences by Day 36.

Animals↗
PubMed1988

Effect of spirogermanium and radiation therapy on the 9L rat brain tumor model.

Spirogermanium (SPG) was investigated in the 9L rat brain tumor model in vivo and in vitro. Used at a single ip dose of 50 or 60 mg/kg or at 5 daily doses of 10 mg/kg, SPG was ineffective in prolonging survival of rats burdened with the intracerebrally implanted tumor, i.e., the median survival time (MST) was the same as that for the controls. Only a schedule of 3 X 20 mg SPG/kg every other day improved the MST compared with controls. Single-dose (20-Gy) radiation therapy (RT, cesium-137 whole-head irradiation) did prolong survival. However, when single-dose SPG was combined with RT (1 hr or 1 day before, or 1 hr after RT), the survival response was worse than after RT alone. When the daily SPG was combined with daily RT (5 doses of 6 Gy), survival was no better than after daily RT alone. In vitro, SPG produces a concentration-dependent, exponential decrease in cell survival as measured by colony formation assay. When combined with radiation, there is an additive effect on cell lethality. Aside from the possibility that SPG does not penetrate the rat brain tumor itself, we have no explanation why SPG shows some activity against human brain tumors and is cytotoxic against 9L cells in vitro, yet is both ineffective by itself and fails to potentiate RT in the 9L rat brain tumor model.

Animals↗
PubMed1987

Comparison of cancer chemotherapeutic agents in asynchronous and synchronous 9L cells.

The cytotoxic activity of various chemotherapy agents was investigated in asynchronous populations of cultured 9L rat brain tumor cells, and as a function of their position in the cell cycle. Representative drugs from the classes of DNA-active agents, alkylating agents, spindle poisons, and antimetabolites were tested. The ability to induce cell lethality in asynchronous populations as a function of drug concentration varied for 1 hr pulse exposures. In order of decreasing cytotoxic activity, DHAQ was the most effective, followed by VCR, VDS, VBL, ADR, BCNU, cis-DDP, BLM, DBD, RZ, and HU. The effect of chemotherapy agents on synchronous 9L cells obtained by mitotic selection also varied with respect to the individual agent and was cell cycle-dependent. Survival age-responses ranged from being minimal to demonstrating significant fluctuations as a function of cell cycle position. For all agents except ADR and HU, the sensitivity of G1 phase was greater than S phase. RZ exhibited essentially a flat age-response. Comparison of the cell cycle age-responses of chemotherapeutic agents to those exhibited by the cytotoxic modalities of radiation and hyperthermia demonstrate several unique differences.

Animals↗
PubMed1987

Radiotherapeutic management of medulloblastoma in a pediatric patient with ataxia telangiectasia.

Ataxia telangiectasia (AT) is a genetic disorder with a predisposition to malignancy. Cells from patients with AT demonstrate an increased sensitivity to ionizing radiation which creates a problem when these patients require treatment for their malignant disease. An eleven-year-old boy with a previous diagnosis of AT was seen in consultation following partial resection of medulloblastoma in the posterior fossa. To estimate how much the conventional radiation dose might have to be reduced, we compared the radiosensitivity of bone marrow myeloid progenitor cells from this patient to that of cells from the marrow of normal individuals, using colony formation in an agar culture assay system as the endpoint (CFU-Cs). Neither radiation dose-survival curve exhibited a shoulder--each displayed an extrapolation number of 0.99. The survival curve of normal cells displayed a steep slope with a D0 of 0.98 Gy (0.83-1.19 Gy, 95% confidence limits); the slope for the AT cells was considerably steeper with a value for D0 of 0.32 Gy (0.29-0.35 Gy). The ratio of D0's indicated that these AT cells were approximately 3X more radiosensitive than normal cells. Based on this, the daily dose was reduced from 1.8 to 0.6 Gy and the radiation was restricted to 25 treatments to the posterior fossa rather than the conventional cranio-spinal treatment. An additional 5 treatments at 1.0 Gy per day were given to the whole brain. The patient's skin responded to these reduced fraction sizes and doses to a similar degree as normal patients' skin following a standard schedule and the patient is doing well nine months after initiation of treatment.

Ataxia Telangiectasia↗
PubMed1986

Investigation of the interaction of cardiotoxic anticancer agents using the fetal mouse heart organ culture system.

The fetal mouse heart organ culture system was utilized in an effort to document and predict the potential cardiotoxic effects of ionizing radiation, Adriamycin (ADR), and Dihydroxyanthraquinone (DHAQ); alone and in combination. These antineoplastic agents have been shown to produce clinical cardiomyopathy which is often dose-limiting. Fetal mouse hearts (gestational day 17) were removed and placed in a culture system of 6-well microtiter plates. A single heart was placed in each well on a piece of aluminium mesh, above the culture medium but bathed by capillary action. The plates were then placed in a 100% oxygen environment and incubated at 37 degrees C. Treatments performed on day 1 after culture were Cs-137 irradiation (10, 20, or 40 Gy); ADR (10, 30, or 100 micrograms/ml); DHAQ (5, 20, or 50 micrograms/ml); or various combinations of drugs and radiation. Hearts were checked every day for functional activity as evidenced by continuous heart best. Untreated hearts beat rhythmically for up to 9 days (average = 6.8 days); treated hearts stopped beating between 2 and 7 days after treatment. Using this endpoint of functional retention time (FRT), dose response curves were obtained for all individual agents. Combinations of ADR and DHAQ (at concentrations that resulted in FRTs of 3.5 days) produced no greater effect than either agent alone. However, the combination of radiation (FRT = 5.3 days) with ADR, DHAQ or both drugs was more effective than was drug alone. This system may help to predict the cardiotoxic effects that result from the use of these drugs and radiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Intraperitoneal bleomycin for ventriculoperitoneal spread of a hypothalamic astrocytoma.

A pediatric patient is presented in whom malignant ascites developed after ventriculoperitoneal shunt placement for a suprasellar astrocytoma. Paracentesis followed by intraperitoneal bleomycin resulted in decreased fluid re-accumulation with minimal side effects. A review of the literature shows that intracavitary chemotherapy, including bleomycin, can result in safe, effective relief of malignant effusion associated with adult tumors. We have demonstrated that such treatment is also applicable to the pediatric population. In this case, the effectiveness of intracavitary bleomycin may be related to its direct action against brain glioma cells. The need for effective treatment of malignant effusions in pediatric patients is growing because of their increased survival time with tumor. We propose that intracavitary bleomycin may provide relief from this potential complication of childhood solid tumors.

Astrocytoma↗
PubMed1985

Comparison of single, fractionated and hyperfractionated irradiation on the development of normal tissue damage in rat lung.

The effect of fractionated thoracic irradiation on the development of normal tissue damage in rats was compared to that produced by single doses. Animals received a single dose of 15 Gy, 30 Gy in 10 daily fractions of 3 Gy each (fractionation), or 30 Gy in 30 fractions of 1 Gy each 3 times a day (hyperfractionation). The treatments produced minimal lethality since a total of only 6 animals died between days 273 and 475 after the initiation of treatment, with no difference in survival observed between the control and any of the 3 treated groups. Despite the lack of lethality, evidence of lung damage was obtained by histological examination. At times less than 180 days after treatment, the lungs of animals receiving a single dose of 15 Gy displayed more severe changes than did animals from either fractionation group. At longer times after treatment (days 261 and 475), the histological appearances within each group were changed, collagen deposits and fibrosis being the most significant observations. Animals that had received either single doses or fractionated doses had more of the pulmonary parenchyma involved than did animals that had received hyperfractionated doses. We conclude that, in the rat lung model, a total radiation dose of 30 Gy fractionated over 14 days produces no more acute lethality nor damage to lung tissue than does 15 Gy delivered as a single dose. However, long-term effects as evidenced by deposits of collagen and development of fibrosis are significantly reduced by hyperfractionation when compared to single doses and daily fractionation.

Animals↗
PubMed1985

Radiation response of human normal and leukemic hemopoietic cells assayed by in vitro colony formation.

The effect of ionizing radiation on the survival of bone marrow cells from patients with acute nonlymphocytic leukemia or from hematologically normal controls was studied using colony formation as an endpoint. A modified agar culture method which incorporated daily feeding with new medium was used to allow the growth of leukemic cell colonies. Analysis of radiation-dose survival curves revealed that normal bone marrow cell populations exhibited a relatively steep slope, with values of D0 ranging from 0.5-1.3 Gy (mean = 0.82 +/- 0.22 Gy). There was essentially no shoulder to the survival curves, with Dq values ranging from less than 0 to 0.3 Gy. The leukemic cells tested displayed survival curves that did not differ qualitatively from those obtained with normal cells, i.e., steep slopes and neglible shoulders. However, the average value of the D0 (0.62 +/- 0.15 Gy) was statistically different (p less than 0.025) than that obtained for the normal cells. The results of these studies may have implications both for the use of radiation therapy for the treatment of malignant hemopoietic diseases, and for total body irradiation prior to bone marrow transplantation.

Bone Marrow↗
PubMed1985

Comparison of the supravital DNA dyes Hoechst 33342 and DAPI for flow cytometry and clonogenicity studies of human leukemic marrow cells.

Human leukemic bone marrow cells were studied by flow cytometry and a colony-forming assay. Two supravital DNA dyes, Hoechst 33342 (H33342) and 4',6-diamidino-2-phenyl indole dihydrochloride (DAPI), were compared in terms of DNA histograms by flow cytometry and toxicity to cells by colony-forming assay. Initially, Chinese hamster ovary (CHO) cells were used, and the optimal staining conditions for the two dyes were determined: 30 min exposure to 10 micrograms/ml at 37 degrees C for H33342 and at 23 degrees C for DAPI. DAPI demonstrated DNA profiles with better coefficients of variation for Go/G1 cells than did H33342. This difference was consistently shown in four additional mammalian cell lines and bone marrows freshly obtained from five patients, four of which were leukemic. Both dyes, in the optimal staining conditions, can suppress the growth of CHO cells with H33342 more toxic than DAPI. In experiments on three leukemic bone marrows, H33342 was shown to be more toxic than DAPI in terms of colony-forming capability. Although there is considerable variation in the degree of the toxicity between different cases, more than 50% of leukemic colony-forming cells can survive after DAPI staining. These data indicate that DAPI is preferable to H33342 for use with human leukemic cells because the staining technique required is less stringent; there is a more homogenous staining of the DNA, and there is less cytotoxicity induced. Supravital staining of DNA with DAPI and viable sorting by flow cytometry should be reasonably possible for functional studies such as colony formation after sorting.

Acute Disease↗
PubMed1984

Interaction of radiation, dihydroxyanthraquinone, and adriamycin on the induction of acute lethality in mice.

The acute lethality induced by combinations of radiations, Dihydroxyanthraquinone (DHAQ), and Adriamycin (ADR) was investigated in mice. Whole-body irradiation produced acute lethality, with an LD-50/30 of approximately 6.5 Gy. ADR and DHAQ produced LD-50/30's of 14 and 4 mg/kg, respectively. When 10 mg/kg doses were fractionated into 5 X 2 mg/kg daily doses, both drugs were equally or more efficient at producing mortality, 90% by day 30. When 4 Gy radiation was combined with 5 mg/kg ADR or 5 mg/kg DHAQ, a response no greater than that produced by drug alone was obtained. However, when 5 mg/kg ADR was administered concomitantly with 5 mg/kg DHAQ, there was a less-than-additive induction of lethality, resulting in only 21% mortality by day 30. Since this response is similar to that seen after ADR only, it would appear that the DHAQ-induced toxicity was protected against. Less-than-additive effects were also observed for combinations of 5 mg/kg ADR with either 2.5 or 10 mg/kg DHAQ; and combinations of 10 mg/kg ADR with either 2.5 or 5 mg/kg DHAQ. If ADR and DHAQ (at doses of 5 mg/kg) were combined but with a 1 day interval between drugs, the protective effect was lost and animals died earlier than after either agent alone. At present, no definite explanation is available for this unusual protective effect of ADR against acute lethality induced by DHAQ.

Animals↗
PubMed1984

Ultrastructural evidence of cardiac damage resulting from thoracic irradiation and anthracyclines in the rat.

The effects of radiation combined with Adriamycin (ADR) or Dihydroxyanthraquinone (DHAQ, NSC 279836) on the induction of cardiomyopathy in the rat were investigated using electron microscopy. Rats were treated with ADR or DHAQ at 2.5, 5.0, or 10 mg/kg ip; thoracic irradiation at 12, 15, 18, 21, or 24 Gy of 25 MV X rays; or a combination of either drug at 5.0 mg/kg plus 15 Gy X rays. Survival times were observed to be linear, inverse functions of the dose of drug or radiation received. Combinations of ADR plus radiation produced an increased lethality while the combination of DHAQ and radiation produced similar lethality as DHAQ alone. Even for treatments that resulted in animal lethality, there was little histological evidence of abnormality observed in heart tissues by light microscopy. On the other hand, electron microscopic examination of cardiac tissues demonstrated dramatic decreases in mitochondrial number and destruction of mitochondrial structure. The treatments could be arranged in order of increasing severity of the damage produced as follows: 5 mg/kg ADR, 15 Gy X ray, 5 mg/kg DHAQ, 5 mg/kg ADR + 15 Gy X ray, 24 Gy X ray, and 5 mg/kg DHAQ + 15 Gy X ray. In several cases, mitochondrial abnormalities were sufficient so as to allow cardiomyopathy to be cited as the cause of death. These results indicate that electron microscopy can be used to document cellular changes that may only be functionally expressed as long-term normal tissue damage or animal lethality. The finding that DHAQ can produce significant cardiotoxicity, and that this cardiotoxicity is enhanced by concomitant thoracic irradiation, suggest caution while this drug is being investigated for clinical use.

Animals↗
PubMed1984

Modification of radiation and dihydroxyanthraquinone-induced cell lethality by cysteamine and N-ethylmaleimide.

The effect of alteration of sulfhydryl levels on the cell lethality induced by ionizing radiation and dihydroxyanthraquinone (DHAQ) was investigated in cultured Chinese hamster V79 cells. DHAQ produces a potentiation of radiation-induced cell lethality, both by increasing the slope and decreasing the shoulder of the survival curve. It has been suggested that DHAQ functions through the production of free radicals which then produce DNA strand breaks and crosslinks, resulting in cytotoxicity. If this mode of action predominates, then one would expect to be able to change the degree of cell kill by modifying conditions such that free radical processes were altered. This was accomplished by the addition of N-ethylmaleimide (NEM) or Cysteamine (CYS) to the culture medium during treatment with DHAQ. It was observed that the combination of DHAQ and NEM did not produce more cytotoxicity than would be expected from an additive interaction. Likewise, CYS did not reduce the cytotoxicity induced by DHAQ. When cells were treated with DHAQ and radiation plus either NEM or CYS, the resultant survival was consistent with an additive interaction between the potentiation of DHAQ for radiation-induced cell kill and the extra effect of NEM or CYS. These results indicate that alterations of sulfhydryl levels do not produce changes in the cytotoxicity induced by DHAQ, nor in the enhancement by DHAQ of radiation-induced lethality. More investigation is required before definite conclusions can be reached as to the mechanisms of action by which DHAQ, alone or in combination with ionizing radiation, induces mammalian cell lethality.

Animals↗
PubMed1984

Effect of dihydroxyanthraquinone on the response of a rat solid tumor to radiation therapy.

Dihydroxyanthraquinone (DHAQ, NSC 279836, a new cancer chemotherapeutic agent presently in clinical trials) was tested, alone and in combination with radiation, for therapeutic effectiveness in a rat solid tumor model. The Walker 256 fibrosarcoma was implanted subcutaneously in the leg via trochar so as to yield palpable tumors within 7-11 days. When tumor diameters reached 1 cm, the animals were treated as follows: as controls; with DHAQ (3.0 mg/kg, i.p.); with 300 KVP x-rays (15 Gy to the tumor-burdened leg); or with a combination of DHAQ and radiation. Tumor diameters were measured three times a week to monitor the response to therapy. DHAQ alone had no effect on tumor growth rate. Radiation alone produced a delay in tumor growth. The combination of DHAQ and radiation resulted in a consistently better therapeutic response than did radiation only, but at only a marginal level of statistical significance (0.05 less than p less than 0.10). However, there were 3/10 long-term survivors (greater than 80 days post treatment) without evidence of tumor in the combination therapy group; whereas all animals in the radiation group died or were sacrificed because of progressive tumor growth by day 71. These results suggest that even though DHAQ is only minimally effective against this rat solid tumor when used alone, there may still be some added therapeutic benefit derived from a combination of DHAQ and radiation therapy.

Animals↗
PubMed1984

Development of normal tissue damage in the rat subsequent to thoracic irradiation and prior treatment with cancer chemotherapeutic agents.

The effect of combined modalities (radiotherapy-chemotherapy) on the development of long-term normal tissue damage was investigated in rats. Animals received single I.P. injections of Hank's balanced saline solution, adriamycin (ADR, 1.0 mg/kg), bleomycin (BLM, 10 units/kg), or dihydroxyanthraquinone (DHAQ, 3.0 mg/kg); and/or irradiation of the chest with 25 MV x-rays (12 Gy) at 0, 43, 93, or 199 days after drug treatment. Only animals treated with DHAQ displayed appreciable toxicity, with more animals dying at less than 200 days when radiation was added at 0 or 43 days. Although animals treated with BLM or radiation exhibited evidence of lung damage (histologically by 199 days and radiographically by 300 days), their survival was not compromised. The simultaneous administration of x-ray and BLM produced enhanced effects as compared to either agent alone. These results demonstrate an enhancement of normal tissue damage by combined treatment with radiation and chemotherapeutic agents, not only for acute toxicity but also for long-term effects. This damage was ultimately expressed as alteration of lung structure (histologically and radiographically) in the case of BLM, and as animal lethality in the case of DHAQ. In addition, there was a reduction in the degree of enhancement observed as a function of the separation in time between treatment with chemotherapeutic agents and subsequent irradiation. These factors should be considered when combined modality therapy is used for treatment of cancer in the thoracic region.

Animals↗
PubMed1984

Angiotensin-I-converting enzyme in cancer patients.

Serum levels of angiotensin-I-converting enzyme (ACE) were assayed before, during, and after radiation therapy in 209 patients receiving treatment for neoplastic disease. Daily fluctuations in the measured ACE levels were minimized by comparing all patient values to that of a simultaneously run sample from a standard source of serum obtained by pooling sera from young, healthy volunteers. Most of the patients tested presented with a normal to low ACE level, with the mean value for all patients being 70% of the standard value. More patients with primary lung cancer displayed values that were low (107 of 120) than did patients with disease outside the lung (44 of 78), this difference being statistically significant at p less than 0.001. In addition, more patients with lung cancer had values less than 70% of the standard than did patients with disease outside the lungs. These initial results suggest that monitoring of serum ACE levels may be useful in the management of patients with malignant disease in the lung.

Female↗