Biomedical subjects

B F Kimler

Publications and source records attributed to B F Kimler.

At least 37 records · Page 2Linked to original sources

PubMed1996

Value of deoxyribonucleic acid ploidy and nuclear morphometry for prediction of disease progression in renal cell carcinoma.

PURPOSE: A retrospective study was performed on 108 patients with localized renal cell carcinoma (pT1 to 3a N0M0) to determine whether ploidy and nuclear morphometry are independent predictive factors in addition to stage and grade. MATERIALS AND METHODS: Deoxyribonucleic acid (DNA) content was analyzed by flow cytometry and nuclear morphometry characterized by 5 nuclear descriptors. A Cox proportional hazards regression model was used to identify significant prognostic factors for disease progression. RESULTS: A model combining tumor stage and grade, DNA ploidy and nuclear minor axis was chosen as optimal with risk of disease progression increased with increasing tumor stage and grade, DNA aneuploidy and increasing nuclear minor axis. CONCLUSIONS: This improved ability to predict disease progression in localized renal cell carcinoma may have important clinical use.

Adult↗

PubMed1996

Identification of a chemoprevention cohort from a population of women at high risk for breast cancer.

In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 213 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women were those with a first degree relative with breast cancer (73%), prior biopsy indicating premalignant breast disease (26%), a history of breast cancer (13%), or some multiple of these risk factors (11%). Median ages of the high-risk and low-risk groups were 44 and 42, respectively. Sixty-three percent of the high-risk and 73% of the low-risk group were premenopausal. Sixty-eight percent of the high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 25%, 36%, and 28% of high-risk subjects but in less than 4% of low-risk subjects (P < .0002). Overexpression of ER and HER-2/neu occurred in 8% and 19%, respectively of high-risk women; nc low-risk women had these abnormalities. Sixty-eight percent of high-risk women and 7% of low-risk women had abnormalities of one or more of these biomarkers exclusive of cytology. Thirty-one percent of high-risk women, but no low-risk women had abnormalities of two or more biomarkers (P = .0004). Biomarker abnormalities were more frequent with increasing cytologic abnormality. Eighteen percent of women with normal cytology, 29% of women with epithelial hyperplasia and 60% of women with hyperplasia with atypia had abnormalities of two or more biomarkers (P = .048 and < .0001, respectively). Restricting the analysis to those three biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 20% of high-risk women with epithelial hyperplasia and 51% of high-risk women with atypical hyperplasia had abnormalities of 2 or more of these 3 biomarkers. At a median follow up of two years, 8 of 213 women have been diagnosed with in situ (n = 5) or invasive (n = 3) cancer. Later detection of neoplasia was associated with prior FNA evidence of atypical hyperplasia (P < .0001) and multiple biomarker abnormalities in the 5 test battery (P = .006) by univariate analysis. By multivariate analysis, development and/or detection of cancer was primarily predicted by atypical hyperplasia (P = .0047) and secondarily by multiple biomarker abnormalities (P = 0.021). Atypical hyperplasia, EGFR, and p53 in breast FNAs have promise as risk markers and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.

Adult↗

PubMed1995

Reduction of tumor necrosis factor-alpha bioactivity by a human ovarian epithelial cancer cell line in vitro.

OBJECTIVE: Our purpose was to determine the ability of an ovarian epithelial carcinoma cell line, Caov-3, to alter the bioactivity of exogenously added tumor necrosis factor-alpha. STUDY DESIGN: Caov-3 cells were cultured for up to 6 days in Dulbecco's modified Eagle's medium containing 10% fetal calf serum. The control and tumor necrosis factor-alpha-treated cells were analyzed for proliferation, distribution throughout the cell cycle by flow cytometry, their ability to release bioactive tumor necrosis factor-alpha by L929 bioassay, and their ability to release immunoreactive tumor necrosis factor-alpha by a specific double sandwich enzyme-linked immunosorbent assay. RESULTS: Tumor necrosis factor-alpha induced a dose- and time-dependent inhibition of cell proliferation accompanied by accumulation of cells in late S and G2/M phases of the cell cycle. Tumor necrosis factor-alpha bioactivity was undetectable in the media of control Caov-3 cell cultures, but these cells exhibited TNF-alpha messenger ribonucleic acid. After culture of the cells for 2 days in the presence of various doses of TNF-alpha (0.1, 1.0, 10, or 100 ng/ml), a significant decline (p < 0.01) in bioactivity was observed in all groups with the exception of 100 ng of TNF-alpha. Further declines in bioactivity were observed 2 and 4 days later. Addition of TNF-alpha to Caov-3 cells did not affect its immunoactivity, and Western blots of media revealed major bands of immunoactivity at approximately 17 kd, the expected molecular size of TNF-alpha. CONCLUSION: These results indicate that Caov-3 ovarian carcinoma cells reduce the bioactivity of TNF-alpha, an important growth regulator, by a novel yet unknown mechanism to escape the modulatory effects of the normal immune response during cancer cell growth.

Animals↗

PubMed1995

Drug-induced hypergastrinemia: absence of trophic effects on colonic carcinoma in rats.

BACKGROUND/AIMS: Published studies suggest that hypergastrinemia stimulates growth of normal or malignant colon tissue. Other studies dispute these findings. This study was designed to test the hypothesis that hypergastrinemia enhances progression or invasiveness of colon cancer. METHODS: Colonic carcinomas were induced in male Sprague-Dawley rats by six weekly intraperitoneal injections of methylazoxymethanol. Four weeks after the last injection of carcinogen, the animals were randomized into four treatment groups, including vehicle control, low- and high-dose omeprazole, and ranitidine. After 10 weeks of treatment, the animals were bled, stomach weights were recorded, and colon tumors were mapped, enumerated, measured, and scored histopathologically by Dukes' classification. Crypt and mucosal heights were determined in colonic mucosa unaffected by tumor. RESULTS: Drug administration induced a sustained hypergastrinemia that did not enhance tumor burden or invasiveness or crypt height/mucosal height ratios. Ranitidine-treated rats consumed less food, weighed less, and developed fewer tumors. This group also had lower crypt and mucosal heights than rats in the vehicle- or omeprazole-treated rats. CONCLUSIONS: The results suggest that endogenous hypergastrinemia induced by these acid-suppressing drugs has no stimulatory effect on colon mucosal growth or progression or biological behavior of experimental rat colon cancer.

Analysis of Variance↗

PubMed1995

Effects of omeprazole on cell kinetics of carcinogen-induced colon tumours in rats.

This study was designed to evaluate the effects of hypergastrinaemia induced via suppression of gastric acid by omeprazole on carcinogen-induced colon cancer in rats. The carcinogen methylazoxymethanol (MAM), 30 mg/kg, was administered intraperitoneally at 6-weekly intervals to Sprague-Dawley rats. Four weeks after the last MAM injection, the first daily dose of omeprazole, 40 mg/kg, was given by gastric gavage to one group of rats, and the rest were given buffered methylcellulose vehicle. After 10 weeks of daily omeprazole or vehicle, the rats were anaesthetized with ether, blood samples obtained, and animals sacrificed. Gastrin levels in serum from omeprazole-treated rats were elevated nearly six-fold. DNA and RNA levels in gastric mucosa were unchanged by omeprazole, but protein content was somewhat reduced. No biochemical or histological changes related to omeprazole treatment were observed in normal colon. The number of tumours, tumour volumes, and total tumour burden were not significantly different in colons of vehicle- or omeprazole-treated rats. Analysis by flow cytometry revealed that the S phase fraction was lower in tumour cells from omeprazole-treated animals; and that the frequency of DNA aneuploidy was also reduced. The results indicate that while omeprazole-induced suppression of stomach acid in rats elevates levels of gastrin in serum, it does not substantially alter the biochemical or cellular characteristics of carcinogen-induced colon tumours.

Animals↗

PubMed1994

Recruitment with high physiological doses of estradiol preceding chemotherapy: flow cytometric and therapeutic results in women with locally advanced breast cancers--a Southwest Oncology Group study.

One theoretical method of increasing chemotherapeutic efficacy in breast cancer is to temporarily increase the number of tumor cells in cycle through hormonal recruitment prior to initiation of chemotherapy. In an effort to determine when and if this could be reliably accomplished, 50 women with locally advanced and/or metastatic breast cancer with known estrogen receptor (ER) status were entered into a serial breast biopsy study designed to measure increases in S-phase fraction (SPF) and proliferative index (PI; S + G2 + M) following administration of a high physiological dose of estrogen via estradiol vaginal suppositories prior to chemotherapy. Blood levels of estradiol were maintained in a range (0.5-5 nM) known to increase SPF in vitro. Compliance with suppository administration was monitored by serial blood sampling. Tumors were sampled at 0, 24, 48, 72, and/or 96 h. Thirty-one ER-positive and 9 ER-negative women had evaluable baseline biopsies and at least 1 subsequent biopsy. An increase was seen for SPF in 20 (69%) and for PI in 23 (79%) of 29 ER-positive patients at 48 h after estrogen initiation (95% confidence intervals, 49-85% for SPF and 60-92% for PI); similar increases were seen at 72 h. Median baseline SPF and PI values in ER-positive patients for whom increases were noted at 48 h were 6.2 and 8.5%, respectively. The median relative increases in these patients were 170 and 100%, respectively, at 48 h. The increases observed at 24 h in 4 (SPF) and 6 (PI) of the 9 ER-negative patients could have occurred by chance alone. Twenty-five of the 28 locally advanced (T4 and/or N2-3) patients achieved a complete response during combined modality treatment (estradiol-chemotherapy, mastectomy, and radiation). At a minimum follow-up time of 42 months, estimated 5-year progression-free and overall survivals are 30 and 49%, respectively, with a median time to progression of 35 months. Twenty-two women had metastatic disease (19 also had locally advanced disease). Thirteen had a complete or partial response, with a median duration of 12 months. Median progression-free and over-all survival times for all metastatic patients are 4 and 17 months, respectively. Estimated 5-year survival for metastatic disease patients is 27%. A high physiological dose of estrogen administered to patients with locally advanced ER-positive tumors can reliably increase the tumor SPF and PI within 48 h.(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗

PubMed1994

Prevalence of aneuploidy, overexpressed ER, and overexpressed EGFR in random breast aspirates of women at high and low risk for breast cancer.

Breast tissue biomarkers which accurately predict breast cancer development within a 10 year period in high risk women are needed but currently not available. We initiated this study to determine 1) the prevalence of one or more breast tissue abnormalities in a group of women at high risk for breast cancer, and 2) if the prevalence of biomarker abnormalities is greater in high risk than in low risk women. Eligible high risk women were those with a first degree relative with breast cancer, prior breast cancer, or precancerous mastopathy. Low risk women were those without these or other major identifiable risk factors. Ductal cells were obtained via random fine needle aspirations and cytologically classified. Biomarkers included DNA ploidy, estrogen receptor (ER), and epidermal growth factor receptor (EGFR). The prevalence of DNA aneuploidy was 30%, overexpression of ER 10%, and overexpression of EGFR 35%, in the 206 high risk women whose median 10 year Gail risk (projected probability) of developing breast cancer was 4.5%. The prevalence of aneuploidy and overexpressed EGFR was significantly higher in the high risk women than in the 25 low risk controls (p < 0.002), whose median 10 year Gail risk was 0.7%. The difference in the prevalence of ER overexpression between high and low risk groups was not statistically significant (p = 0.095). This may be due to the low prevalence of overexpressed ER and the small number of controls. A significant difference was noted in the prevalence of one or more abnormal biomarkers between the high risk and low risk women (p < 0.001). A large prospective trial is needed to determine if one or more of these biomarkers, is predictive of breast cancer development.

Adult↗

PubMed1994

The 9L rat brain tumor model for pre-clinical investigation of radiation-chemotherapy interactions.

The rat 9L gliosarcoma brain tumor model has been used for more than thirty years to investigate a variety of potential therapeutic agents, combinations, schedules, and approaches that might be applicable to the management of high-grade malignant brain tumors in man. When tumor cells are implanted intracerebrally, a solid tumor grows until its mass results in the death of the animal, typically between 20 and 30 days postinoculation. Radiation therapy (either single or fractionated doses) is effective at prolonging survival in a dose-dependent manner. Numerous cancer chemotherapeutic agents, by a variety of doses, schedules, and routes of delivery, have demonstrated therapeutic efficacy in the 9L model. The combination of radiation and agents such as AZQ, BCNU, bleomycin, and cis-platinum has resulted in prolongation of survival that is significantly better than either agent used alone, without exceeding the tolerance of critical normal tissues. These pre-clinical data suggest that combining standard fractionated radiation therapy with appropriate concomitant cytotoxic chemotherapeutic agents might benefit patients with high-grade brain tumors.

Animals↗

PubMed1994

Effect of in utero radiation dose fractionation on rat postnatal development, behavior and brain structure: 3-hour interval.

Effect of In Utero Radiation Dose Fractionation on Rat Postnatal Development, Behavior and Brain Structure: 3-Hour Interval. Neurotoxicology 15(1): 183-190, 1994. We have previously shown that exposure of the rat fetus to ionizing radiation produces dose-dependent (0.25-1.25 Gy) changes in postnatal growth and behavior, and decreases in cerebral cortex thickness. Pregnant rats were exposed to single doses of 0.5 or 1.0 Gy, or to two doses of 0.5 Gy (separated by a 3 h interval) on gestational day 15. Pups were weighed and subjected to behavioral tests (righting reflex; reflex suspension; negative geotaxis; continuous corridor; and length, width, and sine of gait) over postnatal days 7-28. The rats were then sacrificed and brains removed for histology. The fractionated doses produced responses that were generally intermediate between those produced by the single doses and which, by interpolation, could be expressed as equivalent to a single dose between 0.5 and 1.0 Gy. Overall, exposure of the fetal rat to two doses of 0.5 Gy separated by 3 h produced effects equivalent to a single dose of 0.85 Gy. We conclude that fractionation of radiation dose results in less damage to the developing rat cerebral cortex, as measured by postnatal growth, behavioral tests, and morphological assessment.

Animals↗

PubMed1993

Lack of complications in long-term survivors after treatment with Fluosol and oxygen as an adjuvant to radiation therapy for high-grade brain tumors.

PURPOSE: A Phase I/II trial was initiated in 1987 to determine the toxicity/efficacy of the perfluorochemical emulsion Fluosol-DA 20% and 100% oxygen as an adjuvant to conventional radiation therapy for high-grade brain tumors. METHODS AND MATERIALS: Three grade 3 and 15 grade 4 patients received 1 Fluosol administration (8 mL/kg) per week with daily oxygen breathing prior to and during radiation therapy. Megavoltage radiation was delivered to the whole brain at 25 x 1.8 Gy, followed by 10 x 2 Gy to a boost volume, resulting in a total tumor bed dose of 65 Gy in 7 weeks. RESULTS: Of the 18 patients, 10 (nine grade 4, one grade 3) survived more than 1 year postsurgery, six (all grade 4) lived more than 2 years, four of these patients lived more than 3 years, and three patients are alive at times ranging from 250 to 276 weeks. The median survival of the Fluosol group was 75 weeks, not statistically different from 54 weeks for a historical, matched control group. However, a Gehan-Wilcoxon test applied to those patients that survived > 1 year revealed a significant difference (p = 0.0013) in favor of the Fluosol group. Periodic clinical evaluations showed no evidence of any functional or neurological defects that could be attributed to radiation therapy and/or Fluosol. Radiographic studies (computed tomography and magnetic resonance imaging) revealed no structural alterations outside the original tumor volume, and changes within the tumor region were easily assignable to expected effects of tumor, surgery, or radiation alone. CONCLUSION: These results indicate that, although Fluosol/oxygen added to conventional radiation therapy does not enhance survival of patients who succumb to their disease early, it does confer a significant benefit to patients that survive past 1 year. The minimal acute side effects and no long-term deleterious effects suggest that Fluosol/oxygen sensitizes only hypoxic cells, with no effect on well-oxygenated normal tissues within the brain. We have been impressed by the quality of life of the surviving patients following radiation therapy with adjuvant Fluosol+oxygen.

Adolescent↗

PubMed1993

Combination of aziridinylbenzoquinone and cis-platinum with radiation therapy in the 9L rat brain tumor model.

PURPOSE: We evaluated the potentiating effects of aziridinylbenzoquinone (AZQ) and cis-platinum on the prolongation of survival by radiation therapy in a rat brain tumor model. METHODS AND MATERIALS: On day 10 following intracranial inoculation of the 9L gliosarcoma, Fischer 344 rats were treated with radiation therapy (Cesium-137 source irradiator) and/or chemotherapy delivered either systemically (intraperitoneal or intravenous), or intracranially directly into the tumor in a volume of 5 microliters. Increased life spans were calculated relative to the median survival time for the control (ILS-C) or to the median survival time for radiation therapy only (ILS-RT) group. RESULTS: Median survival time for untreated rats was 22 +/- 3 days for seven experiments. Radiation therapy (16 Gy) produced a significant (p < 0.002) improvement in survival, with an average ILS-C of 75 +/- 19%. Systemic AZQ (1 or 5 intravenous injections of 0.5 mg/kg) produced ILS's of 0 and 23%, the latter being significant (p = 0.002). When added to radiation therapy, there were further improvements (ILS-RT's of 47 and 72%), but these were not significant. Intratumor AZQ (40 or 50 micrograms intracranially) produced significant ILS-C's of 30 and 33% (p = 0.01 and 0.0002, respectively). Added to radiation therapy, intracranial AZQ produced improvements (ILS-RT's of 5 and 102%), with only the latter being significantly improved (p = 0.009). Cis-platinum (3 micrograms intracranially) produced ILS-C's of 13 and 6%, neither significantly different from controls. Added to radiation therapy, cisplatinum caused improvements (ILS-RT's of 18 and 64%), with only the latter significant (p = 0.049). CONCLUSION: These results demonstrate that AZQ delivered systemically, and AZQ and cis-platinum delivered intracranially, can produce statistically significant improvements in the survival of rats burdened with the 9L brain tumor. The agents delivered intracranially significantly potentiated the prolongation of survival obtained by radiation therapy. This preclinical evidence suggests that combining radiation therapy with these cytotoxic chemotherapeutic agents may benefit patients with high-grade malignant brain tumors.

Animals↗

PubMed1993

Immune adjuvants for chemotherapy or radiotherapy in the 9L rat brain tumor model.

The therapeutic efficacy and toxicity of three biological response modifiers, Corynebacterium parvum (Cp), Chinese blister beetle extract (CBBE), recombinant human IL-1 alpha (rhIL-1 alpha), used alone or in combination with chemotherapy or radiotherapy, were investigated in the intracerebral (ic) rat 9L brain tumor model. Used alone, Cp (2 mg/rat, ip plus 70 micrograms/rat, ic), CBBE (5 microliters of an ethanol extract, ic), or IL-1 alpha (1 microgram/rat, ic or 1 microgram/rat x 3, q 3 d, ic), had no effect on animal survival compared to the untreated or saline treated controls. When combined with chemotherapy or radiotherapy, the three immunotherapeutic agents did not show any additive effects on survival compared to that observed with systemic BCNU (12 mg/kg), local ic bleomycin (0.25 unit), or local radiotherapy (16 Gy). While ic IL-1 alpha did not produce evident toxicity, there was fatal toxicity caused by ic Cp or CBBE treatment in a few animals. The combination of Cp and bleomycin produced severe neurotoxicity, resulting in the early death of animals. This study demonstrates a lack of efficacy of the nonspecific immune adjuvants IL-1 alpha, Cp or CBBE, used either alone or combined with cytotoxic chemotherapy or radiotherapy, in this rat brain tumor model.

Adjuvants, Immunologic↗

PubMed1993

Radioprotection of mice by dietary squalene.

Male C3H mice were fed a diet containing 2% squalene for 14 d prior to and 30 d subsequent to exposure to 6, 7 or 8 Gy of whole body gamma-irradiation (Cesium-137). After 14 d on squalene-supplemented diet, plasma and jejunal tissue squalene levels were 2X and 15X that of controls. Seven days after irradiation, total white cell counts and total lymphocyte counts were substantially depressed in a radiation dose-dependent manner. Although counts in the squalene group were consistently (18-119%) higher than those in the corresponding dietary control group, the differences between dietary groups at any single dose were not significant. Nuclear area of villus cells in the jejunum of both dietary groups was significantly reduced (20%) by day 11 post-irradiation but the nuclear area in squalene-fed mice was significantly greater (15%) than in controls, before and after irradiation. There were no differences in body weight as a function of either diet or radiation dose prior to the first observations of animal lethality. Animal survival was decreased from 100 to 0% at 30 d post-irradiation by radiation doses of 6-8 Gy, with the greatest difference between dietary groups being observed at 7 Gy (median survival times of 12 and 16 d for control and squalene groups, respectively). Overall, survival of squalene-fed mice was significantly prolonged compared with control-fed mice (P = 0.0054 by censored multiple regression analysis). It is concluded that squalene conferred some cellular and systemic radioprotection to mice receiving these lethal whole-body radiation doses.

Animals↗

PubMed1993

Effect of pentobarbital on normal brain protection and on the response of 9L rat brain tumor to radiation therapy.

The authors attempted to confirm published reports that pentobarbital protects against radiation-induced damage to normal rat brain, as well as enhances radiotherapeutic efficacy in a rat brain tumor model. They evaluated animal survival in 9L gliosarcoma-burdened rats that received whole-brain radiation therapy (16, 24, 32, or 40 Gy) while under intraperitoneal pentobarbital (60 mg/kg) or intramuscular ketamine (60 mg/kg) sedation. The animals were examined at autopsy to attribute death to either intracranial tumor growth or normal brain toxicity in the absence of discernible tumor. There was no difference between the two anesthesia groups regarding the survival of unirradiated animals. Radiation therapy produced a significant dose-dependent prolongation in animal survival, which was limited by the development of normal tissue toxicity at the higher doses. When compared to ketamine anesthesia, pentobarbital anesthesia appeared to offer some protection (not statistically significant) against early (but not late) toxicity at selected radiation doses. A reduction in the number of deaths from tissue toxicity suggested an increased antitumor effect, but again this was not statistically significant. Only in one case was there even a marginal significant difference (p = 0.045) between overall therapeutic efficacy in rats sedated with pentobarbital versus ketamine. While there may be a radioprotective effect of pentobarbital in rat brains without intracranial tumor, there is no conclusive evidence for either radioprotection or significant improvement of radiotherapeutic efficacy in this 9L rat brain tumor model.

Animals↗

PubMed1993

Release of interleukin-1 by human alveolar macrophages after in vitro irradiation.

Therapeutic thoracic irradiation may induce two late pulmonary injury syndromes: radiation pneumonitis and subsequent pulmonary fibrosis. The alveolar macrophage has been considered a radioresistant cell and not a target cell involved in the pathogenesis of either type of radiation-induced lung injury. Alveolar macrophage-derived cytokines, including interleukin-1 (IL-1) and tumor necrosis factor (TNF), have been demonstrated to participate in inflammatory and fibrotic responses in the lung after various other types of lung injury. To evaluate whether the release of cytokines by alveolar macrophages is induced by radiation doses used clinically, alveolar macrophages recovered from nonsmoking volunteers were exposed in vitro to a single dose of 2 Gy and then maintained in culture for 18 h. Culture supernatants and cell lysates were then recovered and analyzed for IL-1 alpha and IL-1 beta by radioimmunoassay. Supernatants of irradiated alveolar macrophages contained significantly increased amounts of IL-1 alpha (P < 0.04) and IL-1 beta (P < 0.02) as well as total IL-1 (IL-1 alpha and IL-1 beta) (P < 0.02) compared to nonirradiated alveolar macrophages. Cell lysates of irradiated alveolar macrophages also contained increased amounts of IL-1 alpha and IL-1 beta, although differences from controls were not significant. The finding of increased release of IL-1 by alveolar macrophages after exposure to a single, clinically relevant dose of radiation suggests that the function of human alveolar macrophages is likely altered during therapeutic use of thoracic irradiation. Whether this release of IL-1 by alveolar macrophages contributes to early lung inflammation induced by thoracic irradiation is unclear.

Adult↗

PubMed1993

Is there an adaptive response to radiation in the developing brain of the fetal rat?

An adaptive response has been demonstrated in certain mammalian cells wherein pre-exposure to a small radiation dose prior to a large dose ameliorates the damage induced by the second dose. We investigated whether a similar response could occur in the developing brain of the fetal rat, and if so, what the optimum interval between the two doses would be. Pregnant rats were exposed to a dose of 0.02 Gy gamma radiation at variable times (1, 3, 6, 12, or 24 h) prior to a second dose of 0.5 Gy on day 15 of gestation. Fetuses were harvested at 6 and 24 h after the second irradiation and standard cellular morphological assessments performed on the developing cerebral cortex. For number of mitotic cells, pyknotic cells, and macrophages, no significant differences were found between any of the groups that had received the priming (0.02 Gy) dose and the group that had not. Significant differences were found between fetuses harvested at 6 h and those harvested at 24 h after the final irradiation for all parameters measured. Thus, while the data were consistent with past research relating to the effects of radiation on the development of the brain of the fetal rat, no evidence for an adaptive response to radiation was found. Whether an adaptive response was indeed absent, or whether the doses and/or intervals used were simply not appropriate for demonstrating it, remains unknown.

Adaptation, Physiological↗

PubMed1993

Effect of in utero irradiation on the postnatal development, behavior, and brain structure of rats: dose fractionation with a 6-h interval.

Based on previous studies showing that exposure of the rat fetus to ionizing radiation produces dose-dependent (0.25-1.25 Gy) changes in postnatal development of behavior and decreases in the thickness of the cerebral cortex, we examined the extent to which dose fractionation would reduce expression of damage. Pregnant rats were exposed to single doses of 0.5 or 1.0 Gy, or to two doses of 0.5 Gy 6 h apart on day 15 of gestation. Offspring were subjected to four behavioral tests on postnatal days 7-28; the rats were then sacrificed and their brains removed and processed for histology. For all end points, the fractionated dose produced an effect that was intermediate between that of the 0.5- and 1.0-Gy doses and which, by interpolation, could be expressed as equivalent to a single dose between 0.5 and 1.0 Gy. The equivalent single dose was not significantly different from the 1.0-Gy dose for negative geotaxis (0.54 Gy), reflex suspension (0.80 Gy), and continuous corridor (0.85 Gy). For sine of the angle of the advance of hind feet (0.58 Gy), width of stride (0.69 Gy), length of stride (0.75 Gy), body weight (0.73 Gy), and cerebral cortex thickness (0.69 Gy), the fractionated dose produced effects significantly different (P < 0.05) from the 1.0-Gy dose. Overall, exposure of fetal rats to two doses of 0.5 Gy separated by 6 h produced effects equivalent to a single dose of 0.70 Gy, as measured by postnatal behavioral tests and morphological assessment of brain structure.

Animals↗

PubMed1992

In vitro growth modulation by L-ascorbic acid of colony-forming cells from bone marrow of patients with myelodysplastic syndromes.

In vitro colony growth was studied on bone marrow cells from 51 patients with myelodysplastic syndromes (MDS), using a cell culture method with the unique feature of daily feeding, in an effort to gain insight into the pathophysiology of MDS and to assess the clinical utility of this cell culture assay. The colony growth pattern of MDS marrow cells is remarkably similar to that of acute myeloid leukemia but quite dissimilar from that of normal marrow, in support of a common pathophysiological mechanism for these two disorders. In particular, L-ascorbic acid (LAA) enhanced colony growth in 30% and suppressed growth in 16% of cases, a finding also similar to that in acute myeloid leukemia, indicating a unique growth requirement which may be explored for therapeutic purposes. Further, these LAA effects have prognostic value, with LAA-sensitive (both LAA-enhanced and LAA-suppressed) cases displaying shorter survivals than LAA-insensitive cases (median survival of 5 months versus 18 months; P = 0.011). This prognostic value is independent of, and more powerful than, bone marrow blasts; the median survival was 18 months for less than 5% bone marrow blasts and 8 months for greater than 5% bone marrow blasts (P = 0.044). These two risk factors can be used together to identify patients with an extremely good or an extremely poor prognosis. This study establishes the clinical usefulness of the LAA effect in MDS as a prognostic factor and provides a new lead to explore in understanding differential biochemical/molecular events and, possibly, a new therapeutic approach to the management of MDS.

Adolescent↗