Biomedical subjects

S Rockwell

Publications and source records attributed to S Rockwell.

At least 73 records · Page 4Linked to original sources

PubMed1992

Preclinical evaluation of Oxygent as an adjunct to radiotherapy.

These studies examine the potential value of a concentrated emulsion of perfluorooctylbromide (perflubron; Oxygent, Alliance Pharmaceutical Corp.) as an adjunct to radiotherapy. The effects of Oxygent on solid tumors were examined using EMT6 mammary tumors in BALB/c mice and BA1112 rhabdomyosarcomas in WAG/rij rats. Treatment with Oxygent plus O2, carbogen (95% O2/5% CO2), or hyperbaric oxygen (HBO) increased the effects of radiation on the tumors. Analyses of tumor cell survival curves and measurements of intratumor pO2 showed that this potentiation reflected an increase in the proportion of well-oxygenated tumor cells. Neither treatment of the animals with carbogen, O2, or HBO alone nor treatment of air-breathing rodents with Oxygent produced changes of similar magnitude. Treatment with a vehicle emulsion containing all the components of Oxygent except the perflubron did not alter tumor radiosensitivity, showing that tumor radiosensitization required the oxygen-transporting perfluorocarbon, and did not result from any biologic or physiologic effects of other components of the emulsion. These studies also examined the effects of Oxygent on the radiation responses of mouse skin and bone marrow. Oxygent selectively increased the radiation sensitivity of tumors relative to these normal tissues, thereby increasing the therapeutic ratio and producing therapeutic gain. Oxygent appears to warrant further testing as an adjunct to cancer therapy.

Animals↗

PubMed1992

Fluosol and hyperbaric oxygen as an adjunct to radiation therapy in the treatment of malignant gliomas: a pilot study.

Several clinical trials have been reported using Fluosol and oxygen breathing as an adjunct to radiation. Theoretical considerations and animal experiments, however, indicate that a combination of perfluorochemicals and hyperbaric oxygen (HBO) increases tumor oxygenation and radiation response to a greater extent than is seen either with a perfluorochemical and normobaric oxygen or with HBO alone. This is the first report of a pilot study of the use of Fluosol and HBO with radiation in humans. Twenty patients with anaplastic astrocytoma or glioblastoma multiforme were treated in a phase I trial of radiation with Fluosol and HBO at three atmospheres. Total Fluosol dose was escalated from 42 ml/kg in six courses to 80 ml/kg in four courses. Patients were irradiated in an HBO chamber with 600 cGy weekly fractions following Fluosol administration. Sixteen patients completed treatment; no interruption was necessitated by treatment toxicity. The addition of Fluosol/HBO did not increase the incidence of HBO related toxicities. No significant chronic toxicities were seen. This pilot study demonstrates that Fluosol and HBO can safely be used as an adjunct to radiation in the treatment of human tumors.

Adult↗

PubMed1992

Effect of 2',2'-difluorodeoxycytidine on the viability and radiosensitivity of EMT6 cells in vitro.

EMT6 mouse mammary tumor cells were used to examine the cytotoxic effects of 2',2'-difluorodeoxycytidine (gemcitabine; dFdC) alone and in combination with radiation. The cytotoxicity of dFdC differed from that of most antimetabolites. The concentration-response curve for exponentially growing cells treated for 4 hr with various drug concentrations was exponential down to a surviving fraction of 0.05; thus, dFdC appeared to kill cells in all phases of the cell cycle, rather than killing only the S-phase cells that compose approximately 50% of the cell population. High concentrations of dFdC were toxic to cells in plateau phase EMT6 cultures, as well as to cells in rapidly proliferating cultures. These findings are thought to reflect the unusual cellular pharmacokinetics of the compound. Treatment of exponentially growing cultures with dFdC before, during, and after irradiation was extremely effective in killing the cells; the survival curves for cells treated with drug plus radiation were statistically compatible with either additive cytotoxicity or a synergistic effect (i.e., radiosensitization by dFdC). These studies also provided evidence that dFdC released by dying cells could produce delayed cytotoxic effects on cells not treated directly with dFdC. These data provide several bases for expecting beneficial therapeutic effects from antineoplastic regimens combining dFdC plus radiation.

Animals↗

PubMed1992

Use of hypoxia-directed drugs in the therapy of solid tumors.

Solid tumors in experimental animals and human patients contain areas in which transient or persistent perfusion deficits lead to the development of hypoxia, low pH, and nutritional deprivation. These microenvironmental inadequacies induce resistance to ionizing radiation and to many antineoplastic drugs, but also offer mechanisms that can be used to target certain drugs to solid malignancies. Regimens incorporating hypoxia-directed drugs as adjuncts to radiotherapy or conventional chemotherapy can be used to increase the therapeutic ratio by increasing local tumor control without producing a concomitant increase in toxicities to normal tissues.

Alkylating Agents↗

PubMed1991

Distribution of porfiromycin in EMT6 solid tumors and normal tissues of BALB/c mice.

The distribution of porfiromycin was studied in BALB/c mice bearing EMT6 mammary tumors. The levels of 3H in blood and most tissues peaked approximately 15 minutes after intraperitoneal injection of [3H]porfiromycin. The levels of radioactivity present in most of the tissues and in the tumors were similar at 4 hours and 24 hours after administration. Most of the normal tissues showed uniform, low grain densities when analyzed by autoradiography; the liver and the small intestine had the highest labeling densities. Only kidney, bladder, and tumor showed differential distributions of grains from [3H]porfiromycin. In the kidney, higher grain counts were found in cortex than in medullary regions; grains were uniformly distributed within each region. In the bladder, the highest labeling densities were found in regions near the lumen. Tumor regions that had some necrotic features or regions of necrosis that included some viable cells showed higher labeling intensities than healthy-looking tumor regions, probably because the abnormal microenvironments in these regions led to increased rates of activation of porfiromycin to electrophilic species. These findings show that porfiromycin can reach and be activated in tumor regions containing cells resistant to many chemotherapeutic agents and to x rays. The results also support the concept that agents such as porfiromycin can target cells in specific microenvironmental subpopulations of solid tumors.

Animals↗

PubMed1991

Evaluation of BA1112 rhabdomyosarcoma oxygenation with microelectrodes, optical spectrophotometry, radiosensitivity, and magnetic resonance spectroscopy.

We studied tumor tissue oxygenation in the BA1112 rhabdomyosarcoma using micro-electrode pO2 measurements, optical spectrophotometry, analyses of cell survival after irradiation, and 31P magnetic resonance spectroscopy (MRS). Studies were carried out in WAG/Rij/Y rats breathing normoxic, hypoxic, and hyperoxic gas mixtures with and without iv administration of perfluorochemical. Significant changes in tissue oxygenation and metabolic status were found when pO2 values, optical measurements of hemoglobin saturation and cytochrome a, a3 reduction-oxidation, radiation cell survival determinations, and MRS measurements of phosphometabolite ratios were obtained in rats breathing different gas mixtures. Inhalation of 100% O2 caused increases in tumor pO2, hemoglobin saturation, cytochrome a, a3 oxidation, tumor radiosensitivity, and PCr/Pi, NTP/Pi, and PDE/Pi ratios. Such changes were augmented by pretreatment with iv perfluorochemicals. Inhalation of hypoxic gas mixtures resulted in reductions in the above parameters. These results indicate that tissue oxygenation can be manipulated reproducibly in the BA1112 rhabdomyosarcoma and suggest that 31P MRS can be used to monitor changes in tumor oxygenation in this model system.

Animals↗

PubMed1991

Modulation of tumor oxygenation and radiosensitivity by a perfluorooctylbromide emulsion.

The effect of a concentrated perfluorooctylbromide emulsion (Oxygent) on the radiosensitivity and oxygenation of solid tumors was examined using EMT6 mammary tumors in BALB/c mice and BA1112 rhabdomyosarcomas in WAG/rij rats. Treatment with Oxygent plus carbogen or oxygen breathing increased the radiosensitivity of both tumors. Analysis of tumor cell survival data and polarographic measurements of intratumoral pO2 indicated that this potentiation reflected an increase in the proportion of well-oxygenated tumor cells. Treatments with carbogen breathing alone, with Oxygent plus air-breathing, or with a vehicle emulsion containing all the components except the perfluorocarbon did not produce comparable improvements in tumor radiosensitivity. Concentrated perfluorooctylbromide emulsions appear to warrant further development and preclinical testing as adjuncts to cancer therapy.

Animals↗

PubMed1991

Effect of host age on microenvironmental heterogeneity and efficacy of combined modality therapy in solid tumors.

The implications of microenvironmental heterogeneity in solid tumors for combined modality therapy were assessed by comparing the microenvironmental profiles and therapeutic responses of EMT6 tumors implanted into young and aging mice. The radiobiological hypoxic fraction of tumors in aging mice was shown to be 41% (95% CL, 28-60%), while that in young adult hosts is 19% (95% CL, 14-25%). These microenvironmental differences were also seen in perfusion studies and in studies of the intratumoral pH and pO2 in young and aging mice. The therapeutic importance of microenvironmental factors can be examined in this system, as the tumor cells per se are identical, but the proportions of tumor cells in adverse microenvironments are different. Studies described here show that mitomycin C, an agent with selective toxicity to hypoxic cells, produced greater antineoplastic effects in tumors in aging mice when used alone or as an adjunct to radiation. Combined-modality regimens incorporating agents selectively toxic to hypoxic cells may be especially valuable in improving the results of radiotherapy in tumors in which the tumor-host interactions have resulted in unusually large hypoxic fractions.

Acid-Base Equilibrium↗

PubMed1991

Synthesis and evaluation of some nitrobenzenesulfonamides containing nitroisopropyl and (ureidooxy)methyl groups as novel hypoxic cell selective cytotoxic agents.

Basic nitrobenzenesulfonamides containing nitroisopropyl and (ureidooxy)methyl groups were prepared and evaluated as novel hypoxic cell selective cytotoxic agents. In vitro, N-(2-aminoethyl)-N-methyl-3-nitro-4-(1-methyl-1-nitroethyl)benzene sulfonamide hydrochloride (11) proved to be preferentially toxic to hypoxic EMT6 mammary carcinoma cells. At 1 mM concentration in vitro, 11 reduced the surviving fraction of these hypoxic cells to 3 x 10(-3) with no effect on aerobic cells. In radiation experiments, 11 appeared to function as a hypoxic cell radiosensitizer as well as a selective cytotoxic agent. However, administration of 11 at 200 mg/kg ip or 100 mg/kg iv to BALB/c mice implanted with solid EMT6 tumors produced no evidence of significant in vivo cytotoxic or radiosensitizing activity. N-Methyl-N-[2-(methylamino)ethyl]-3-nitro-4- [(ureidooxy)methyl]benzenesulfonamide hydrochloride (20) showed slight differential toxicity toward EMT6 cells at 3 mM concentration and radiosensitizing activity comparable to misonidazole at 1 mM concentration.

Animals↗

PubMed1991

Isolation, identification, and assay of [3H]-porfiromycin adducts of EMT6 mouse mammary tumor cell DNA: effects of hypoxia and dicumarol on adduct patterns.

[3H]-(N-la-methyl) Porfiromycin (POR) was employed to detect and identify the radiolabeled mono- and bis-adducts formed in living EMT6 mouse mammary tumor cells under different conditions. To provide authentic standard adducts, calf-thymus DNA was treated with POR under reductive activation, then digested to nucleosides and POR-nucleoside adducts. The three major adducts formed were isolated by HPLC and authenticated. Two were mono-adducts, composed of deoxyguanosine linked at its N2-position to C-1 of POR and of 10-decarbamoyl POR. The third was a bis-adduct, in which POR was crosslinked to two deoxyguanosines at their N2-positions. DNA from [3H]-POR treated EMT6 cells was digested an analyzed by HPLC. DNA-associated label was located in thymidine and in two mono-adducts and one bis-adduct identical to those described above. Label in thymidine resulted from N-demethylation of POR and reincorporation of label into new thymidylate residues. Adducts were formed more abundantly in hypoxia than in air. In addition, the mono-adduct to crosslink ratios were different, approximately 1:1 and 2:1 for hypoxic and aerobic cells, respectively. The different patterns of alkylation in air and hypoxia may be related to the greater toxicity of POR in hypoxia. When cells were treated simultaneously with POR and dicumarol, adduct levels were lower, and a new, unknown adduct was observed primarily under hypoxia; these changes may be related to the altered toxicity of POR in the presence of dicumarol. The HPLC assay detected simultaneously the full array of stable mono- and bis-adducts in DNA with good sensitivity (greater than or equal to 2 x 10(6) adducts/nucleotide) and excellent reproducibility. This assay should be generally applicable to all cells and tissues when MC or POR with high specific radioactivity can be employed.

Alkylation↗

PubMed1991

Activity of C-7 substituted cyclic acetal derivatives of mitomycin C and porfiromycin against hypoxic and oxygenated EMT6 carcinoma cells in vitro and in vivo.

A series of cyclic acetal derivatives of mitomycin C (MC) and porfiromycin (POR) were tested for their ability to kill hypoxic and oxygenated EMT6 tumor cells. Amino methyl acetal and thioacetal substitutions at C-7 of MC and POR dramatically increased the cytotoxicity of the compounds to hypoxic EMT6 tumor cells in vitro but had little effect on the aerobic toxicities. In contrast, a methyl substitution at N1a markedly decreased the aerobic cytotoxicities of the compounds but did not alter the hypoxic cytotoxicities. The POR acetal, BMY-42355, had the largest differential between hypoxic and aerobic cytotoxicities yet observed among MC analogs. Preliminary studies in mice showed that BMY-42355 had good antineoplastic activity when used alone or in combination with radiation and was less toxic than POR; the therapeutic ratio of this compound in these initial studies was higher than those of either MC or POR.

Animals↗

PubMed1991

Diarylsulfonylureas and radiotherapy. I. In vitro studies with N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)-urea (Sulofenur).

The effects of proliferative state and environmental factors on the cytotoxicity of N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)-urea (Sulofenur) were examined using EMT6 mouse mammary tumor cells in monolayer cultures. The toxicity of Sulofenur was at least as great in quiescent, plateau phase cultures as in exponentially growing cultures. Acute hypoxia during treatment did not alter the efficacy of the drug. The pH of the culture medium was a critical determinant of cytotoxicity; survival decreased progressively as the pH of the culture medium decreased from 7.0 to 6.0. High concentrations of Sulofenur appeared to potentiate the cytotoxic effects of x-rays. The cytotoxicity of Sulofenur to quiescent cells, the enhanced cytotoxicity at acutely lowered pH, and the interactions between the drug and radiation all suggest that Sulofenur and other diarylsulfonylureas warrant further examination as agents for use in combination with radiotherapy for the treatment of solid tumors.

Animals↗

PubMed1991

Cytotoxicity and DNA crosslinks produced by mitomycin analogs in aerobic and hypoxic EMT6 cells.

Several mitomycin antibiotics were evaluated for their capacities to kill EMT6 tumor cells and to produce DNA crosslinks under conditions of oxygenation and hypoxia. The agents examined included mitomycin C, porfiromycin, and the 7-aminomethyl dithioacetal derivative of mitomycin C (BMY-43324), all of which caused greater kill of hypoxic cells than of their oxygenated counterparts; the N,N'-dimethylaminomethylene derivative of mitomycin C (BMY-25282), which was considerably more cytotoxic under oxygenated conditions than in hypoxia; and the N,N'-dimethylaminomethylene derivative of porfiromycin (BL-6783), which was equal in its toxicity to hypoxic and oxygenated cells. All of these agents produced DNA crosslinks in EMT6 cells, as measured by alkaline elution. The number of crosslinks required to produce a given amount of cell kill was similar, regardless of the mitomycin employed or the degree of oxygenation, suggesting that the crosslinking of DNA was a major lesion in the cytodestructive action of the mitomycins.

Aerobiosis↗

PubMed1991

Effect of deficiencies in DNA repair on the toxicity of mitomycin C and porfiromycin to CHO cells under aerobic and hypoxic conditions.

A wild type Chinese hamster cell line (AA8) and three repair-deficient sublines of AA8 (EM9, UV4, and UV5) were used to study the nature of the cytotoxic lesions produced by the bioreductive alkylating agents mitomycin C and porfiromycin under aerobic and hypoxic conditions. The sensitivities of the repair-deficient sublines to the drugs varied markedly: EM9 was similar to AA8, whereas UV4 was exquisitely sensitive and UV5 was of intermediate sensitivity. Moreover, both the relative toxicities of the two drugs and the relative toxicities of each drug under aerobic and hypoxic conditions varied for the different cell lines. These data suggest that there are differences in the spectra of toxic lesions produced by mitomycin and porfiromycin and that there are differences in the lesions produced by these drugs under aerobic and hypoxic conditions.

Aerobiosis↗

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

Enhanced IUdR radiosensitization by 241Am photons relative to 226Ra and 125I photons at 0.72 Gy/hr.

The dependence of IUdR radiosensitization on photon energy was investigated by irradiating Chinese hamster cells in vitro under aerobic conditions at a dose rate of 0.72 Gy/hr which is typical of temporary brachytherapy implants. It had been observed previously that the IUdR radiosensitization with the 60 keV photons from 241Am is about 1.5 times greater than that with 830 keV (average) photons from 226Ra. It was hypothesized that the enhanced IUdR radiosensitization for 60 keV photons was a result of a larger production of Auger electron cascades from the filling of K-shell vacancies in the iodine atoms, which have a K-shell binding energy of 33.2 keV. Since most of the photons from a 125I source have energies below 33.2 keV, it would be expected that IUdR radiosensitization with 28 keV (average) photons from 125I and 830 keV (average) photons from 226Ra would both be smaller than the radiosensitization with the 60 keV photons from 241Am. To test this hypothesis we compared IUdR radiosensitization for 226Ra, 241Am, and 125I at 0.72 Gy/hr, using Chinese hamster lung cells in vitro. The measured survival curves led to RBEs of 1.20 +/- 0.10 and 1.30 +/- 0.11 for 241Am and 125I photons relative to 226Ra; to IUdR radiosensitization factors at a 10(-5) M concentration of 1.35 +/- 0.11, 1.67 +/- 0.09, and 1.47 +/- 0.08 for 226Ra, 241Am, and 125I, respectively; and to radiosensitization factors at a 10(-4) M concentration of 1.89 +/- 0.16, 3.04 +/- 0.13, and 2.48 +/- 0.17 for 226Ra, 241Am, and 125I, respectively. These results indicate that IUdR produces significant radiosensitization with all three isotopes (226Ra, 241Am, and 125I) for continuous low dose rate irradiations at 0.72 Gy/hr. Also, we observed greater radiosensitization with 241Am photons compared to 226Ra on the higher energy side and to 125I on the lower energy side. These findings support the concept that photon-induced Auger electrons produce a significant increase in IUdR radiosensitization when photons with energies just above the K-edge of the iodine atom are employed for continuous low dose rate irradiations. These findings suggest that regimens combining IUdR infusion with temporary brachytherapy implants using low energy photons in relatively quiescent sites such as brain tumors may have clinical potential, and indicate the need for rigorous preclinical evaluation of this approach.

Americium↗

PubMed1990

Soft-tissue sarcomas: detection of metabolic heterogeneity with P-31 MR spectroscopy.

Regional variations in metabolic parameters derived with multivoxel, localized phosphorus-31 magnetic resonance (MR) spectroscopy in spontaneous human-soft-tissue sarcomas were compared with variations in the same parameters in normal human legs. In addition, multivoxel P-31 MR spectroscopy of transplanted rodent sarcomas and microelectrode measurement of pH and PO2 in several locations within them were performed, and, when appropriate, results were compared with the clinical data. Striking voxel-voxel variability in parameters derived with P-31 spectroscopy was found in tumors, with less marked variability seen in normal legs. In the rodent tumors, spatial variations also were found in pH and PO2 measured by means of microelectrodes. These data are consistent with the results of regional measurements in tumors by means of other methods and suggest that clinical MR spectroscopic studies of tumors may need to consider the variability within malignant lesions.

Animals↗

PubMed1990

Effects of a perfluorochemical emulsion on the response of BA1112 rat rhabdomyosarcomas to continuous low-dose-rate irradiation.

The effects of the combination of a perfluorochemical emulsion (Fluosol DA, 20%) and carbogen (95% O2, 5% CO2) on the response of BA1112 rat rhabdomyosarcomas to continuous low-dose-rate irradiation were examined. Tumors were irradiated locally in unrestrained, unanesthetized rats at a dose rate of 0.98 Gy/h, using a specially designed 241Am irradiator system. Cell survival was measured using a colony formation assay. The tumor cell survival curves were fitted to linear relationships of the form ln S = - alpha D, where alpha for air-breathing rats was 0.104 +/- 0.005 Gy-1, as compared to 0.137 +/- 0.009 Gy-1 for rats treated with Fluosol plus carbogen. The increase in the slope of the survival curve produced by the treatment with Fluosol and carbogen was highly significant with a P value of 0.0015. The radiosensitization factor for the combination of Fluosol/carbogen plus continuous low-dose-rate irradiation was 1.32 +/- 0.11. Slightly less radiosensitization was observed with continuous low-dose-rate irradiation than in previous experiments using acute high-dose-rate irradiation. The diminished sensitization with Fluosol/carbogen during continuous low-dose-rate irradiation probably reflects the intrinsically lower oxygen enhancement ratio (OER) of low-dose/low-dose-rate irradiation, reoxygenation of the tumors during the prolonged treatment times used for continuous low-dose-rate irradiation, and the decrease in the levels of circulating perfluorochemicals during the 30-h irradiations. More importantly, the significant level of radiosensitization observed in the experiments with continuous low-dose-rate irradiation suggests that hypoxic cells persist in BA1112 tumors during continuous low-dose-rate irradiations and that the response of these tumors to continuous low-dose-rate irradiation can be improved by adjunctive treatments which oxygenate these radioresistant hypoxic tumor cells.

Americium↗