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R W Howell

Publications and source records attributed to R W Howell.

At least 37 records · Page 2Linked to original sources
PubMed1997

Design and performance characteristics of an experimental cesium-137 irradiator to simulate internal radionuclide dose rate patterns.

UNLABELLED: When radionuclides are administered internally, the biological effect can depend on the total absorbed dose and the rate at which it is delivered. A 137Cs irradiator was designed to deliver dose-rate patterns that simulate those encountered in radionuclide therapy. METHODS: An 18-Ci 137Cs irradiator was fitted with a computer-controlled mercury attenuator that facilitated changes in dose rates as desired. The absorbed dose and dose rates were calibrated with MOSFET dosimeters customized for low dose-rates. RESULTS: Initial dose rates ranging from 0.01-30 cGy/hr can be delivered depending on the location of the cage in the irradiator and the thickness of the mercury in the attenuator system. To demonstrate the irradiator system's capability to deliver dose-rate patterns encountered in radionuclide therapy, a simulation was performed where the dose rate initially increased exponentially followed by an exponential decrease in the dose rate. CONCLUSION: The irradiator system is well-suited to expose small animals to any dose-rate pattern, thereby facilitating calibration of biological dosimeters (e.g., cell survival, chromosome aberrations), which can be used to measure the absorbed dose to a target tissue after administration of radionuclides.

Animals↗
PubMed1996

[125I/127I]iodoHoechst 33342: synthesis, DNA binding, and biodistribution.

An iodinated analog of the DNA-minor-groove-binding agent Hoechst 33342 has been synthesized and evaluated for DNA binding and tumor targeting. The bis-benzimidazole ring system of the title compound was constructed from the piperazinyl terminus via a Pinner-type cyclization followed by oxidative cyclization of the diamine Schiff base. To synthesize radioiodoHoechst 33342, (trimethylstannyl)Hoechst 33342 was prepared by the same strategy and subjected to mild radioiododestannylation in the presence of lactoperoxidase. After purification by HPLC, the radiochemical was separated in carrier-free form with > 85% radiochemical yield and > 99% chemical and radiochemical purity. Fluorescence spectrometric analysis of the binding of iodoHoechst 33342 to calf thymus DNA gave an equilibrium association constant (Ka) of 2.57 x 10(7) M-1 comparable to the Ka value of Hoechst 33342. Fluorescence microscopy of viable V79 cells demonstrated that the iodinated dye stained the nuclei with avidity similar to that of the noniodinated dye. The biodistribution of [125I]-iodoHoechst 33342 in LS174T tumor-bearing athymic mice 4 h postadministration showed a tumor uptake of 3-4% injected dose per gram (ID/g), tumor/blood ratio of 6-8, and tumor/ nontumor ratios above unity for most organs. A low thyroid uptake (approximately 2% ID/g) indicated that the radiochemical did not deiodinate and was stable in vivo.

Animals↗
PubMed1996

Effects of a 1.5-Tesla static magnetic field on spermatogenesis and embryogenesis in mice.

RATIONALE AND OBJECTIVES: There is a trend toward the use of higher magnetic field strengths in magnetic resonance imaging procedures. Considering this trend and the lack of consensus on the biologic effects of static magnetic fields, it is of considerable interest to examine the biologic effects of a 1.5-tesla (T) static magnetic field on spermatogenesis and embryogenesis in mice. METHODS: Male and pregnant female Swiss Webster mice were exposed to a 1.5-T static magnetic field for 30 minutes. Effects on spermatogenesis in male mice were investigated by counting testicular spermheads and epididymal spermhead shape-abnormalities as a function of time after exposure. Pregnant female mice were exposed to the field at the two-cell embryo stage, sacrificed immediately, and the ability of these preimplantation embryos to mature into blastocysts was examined in vitro. RESULTS: Exposure to the static 1.5-T magnetic field caused a statistically significant reduction (15%) in testicular sperm on the 16th and 29th days after exposure. However, the increase in spermhead shape abnormalities above normal control values was minimal. A substantial effect was noted on the development of preimplantation embryos with a survival fraction of 0.56 compared with controls. CONCLUSIONS: A 30-minute exposure to a 1.5-T static magnetic field appears to cause some deleterious effects on spermatogenesis and embryogenesis in mice.

Animals↗
PubMed1996

Radioprotection by DMSO against the biological effects of incorporated radionuclides in vivo--Comparison with other radioprotectors and evidence for indirect action of Auger electrons.

Dimethyl sulfoxide (DMSO) was studied for its capacity to protect against the biological effects of chronic irradiation by incorporated radionuclides. Spermatogenesis in mice was used as experimental model and spermatogonial cell survival was the biological endpoint. DMSO was injected intratesticularly 4 h prior to a similar injection of the radiochemical and the spermhead survival determined. Iodine-125 was localized in either the cytoplasm (H125IPDM) or in the DNA (125IUdR) of the testicular cells. Protection was observed against the high-LET type effects of DNA-bound 125I as well as the low-LET effects of cytoplasmically localized 125I with dose modification factors (DMF) of 3.1+/-1.0 and 4.4+/-1.0 respectively. No protection (DMF = 1.1+/-0.1) was observed against the effects of high-LET 5.3 MeV alpha particles of 210Po. The present findings provide supporting evidence that the mechanism responsible for the extreme biological damage caused by DNA-bound Auger emitters is largely radical mediated and therefore indirect in nature.

Animals↗
PubMed1996

Calculation of equivalent dose for Auger electron emitting radionuclides distributed in human organs.

Radionuclides that emit Auger electrons can be extremely radiotoxic depending on the subcellular distribution of the radiochemical. Despite this, ICRP 60 provides no guidance in the calculation of equivalent dose H(T) for Auger electrons. The recent report by the American Association of Physicists in Medicine recommends a radiation weighting factor wR of 20 for stochastic effects caused by Auger electrons, along with a method of calculating the equivalent dose that takes into account the subcellular distribution of the radionuclide. In view of these recommendations, it is important to reevaluate equivalent doses from Auger electron emitters. The mean absorbed dose per unit cumulated activity (S-value) from Auger electrons and other radiations is calculated for ninety Auger-electron-emitting radionuclides distributed in human ovaries, testes and liver. Using these S-values, and the formalism given in the recent AAPM report, the dependence of the organ equivalent doses on subcellular distribution of the Auger electron emitters is examined. The results show an increase in the mean equivalent dose for Auger electron emitters when a significant fraction of the organ activity localizes in the DNA.

Female↗
PubMed1996

Antioxidant effects of vitamin C in mice following X-irradiation.

The influence of supplemental vitamin C on the survival of nucleated bone marrow cells was examined in Swiss Webster mice following whole-body sublethal X irradiation (3.5 Gy). The vitamin protected these cells by a factor of 1.7 when cell count per tibia was taken as the biological end point. However, in studies with lethal whole-body irradiation (9 Gy) and 30 day survival as the end point, supplemental ascorbic acid (AA) had no significant effect on the biological outcome. Based on these studies, it appears that vitamin C is effective in protecting the nucleated cells at lower doses, but not at lethal doses. Studies on the mechanism of radioprotection by vitamin C at sublethal doses were carried out by following the response of endogenous AA and glutathione levels to X irradiation (3.5 Gy) on mice fed with regular as well as vitamin C rich diet. The results suggest that i) a glutathione controlled feedback mechanism regulates the plasma AA levels in mice; ii) the role of vitamin C against radiation damage is not only in the initial stages of radical scavenging but also in cellular redox processes mediated by glutathione.

Animals↗
PubMed1995

Generalized approach to absorbed dose calculations for dynamic tumor and organ masses.

UNLABELLED: Tumor absorbed dose calculations in radionuclide therapy are presently based on the assumption of static tumor mass. This work examines the effect of dynamic tumor mass (growth and/or shrinkage) on the absorbed dose. METHODS: Tumor mass kinetic characteristics were modeled with the Gompertz equation to simulate tumor growth and an additional exponential term to accommodate tumor shrinkage that may result as a consequence of therapy. RESULTS: Correction factors, defined as the ratio of the absorbed dose, which was calculated by considering tumor mass dynamics, to the absorbed dose, which was calculated by assuming static mass, are presented for 1- and 100-g tumors with different tumor mass kinetics. The dependence of the correction factor on the effective half-life Te of the radioactivity in the tumor and the tumor shrinkage half-time Ts was examined. The correction factors for the 1-g tumor were > 1 for short Ts and Te. In contrast, the correction factor was less than 1 for long Ts ( > 9 days). The dose correction factors for the 100-g tumor were > 1 for all Ts and Te. Finally, the dosimetric method for dynamic masses is illustrated with experimental data on Chinese hamster V79 multicellular spheroids that were treated with 3H. CONCLUSION: Correction factors as high as about 10 are likely when Te and Ts are short. As Ts increases beyond 20 days, the importance of dynamic mass diminishes because most of the activity decays before the mass changes appreciably. In some cases, mass dynamics should be taken into account when the absorbed dose to tumors is estimated.

Animals↗
PubMed1995

Kinetics and dosimetry of thallium-201 in human testes.

UNLABELLED: Thallous chloride (201Tl) is a well-known imaging agent. It has been shown to accumulate in the testes. In view of this, the testicular kinetics of 201Tl is investigated in humans and the absorbed dose to the organ calculated. METHODS: Thallous chloride 201Tl was injected intravenously into four patients for myocardial perfusion studies. After clinical evaluation, the testicular uptake and clearance of 201Tl were monitored for about 1 wk using a gamma camera. RESULTS: Testicular uptake of 201Tl was rapid with a mean biological uptake half-time of 0.67 hr and mean biological clearance half-time of 280 hr. The mean maximum testicular uptake of 201Tl was about 0.4% of the injected activity. These data were utilized to calculate the average absorbed dose to the testes. The absorbed dose to the testes was calculated to be 3.5 x 10(-4) Gy/MBq (1.3 rad/mCi) of injected activity. CONCLUSION: When the relative biological effectiveness of the Auger emitter 201Tl is taken into account, the equivalent dose to the testes is 9.5 x 10(-4) Sv/MBq (3.5 rem/mCi).

Adult↗
PubMed1995

Radioprotection against biological effects of internal radionuclides in vivo by S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET).

UNLABELLED: Radionuclides employed in diagnostic and therapeutic nuclear medicine impart radiation energy to tissue over an extended period of time, which depends on the physical half-life and the biological properties of the radiochemical employed. It is therefore important to examine the capacity of chemical radioprotectors to mitigate damage caused by chronic irradiation by incorporated radionuclides. METHODS: Spermatogenesis in mouse testis is used as the experimental model, and spermatogonial cell survival as measured by testicular spermhead count is the biological end point. The capacity of S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET) to mitigate radiation damage caused by chronic irradiation by the radiochemicals 125IUdR, H125IPDM and 210Po-citrate, is investigated. RESULTS: The radioprotection provided by AET is substantial and similar for both of the radioiodinated compounds with dose modification factors (DMF) of 4.0 +/- 1.2 for 125IUdR and 3.4 +/- 0.4 for H125IPDM. In contrast, the damage caused by 210Po alpha particles is protected against to a lesser degree (DMF = 2.4 +/- 0.5). CONCLUSION: The present radioprotection data for AET, in conjunction with our earlier findings for the chemical protectors cysteamine and vitamin C in the same experimental model, suggest that such compounds may be clinically useful as mitigating agents against biological damage caused by incorporated radionuclides. The observed DMFs for AET also support our earlier premise that the mechanism by which DNA-incorporated Auger emitters impart biological damage is primarily radical mediated, and hence indirect in nature.

Animals↗
PubMed1994

Bis-benzimidazole dyes, Hoechst 33258 and Hoechst 33342: radioiodination, facile purification and subcellular distribution.

A simple HPLC method is presented for the purification of DNA binding bis-benzimidazole dyes Hoechst 33258, Hoechst 33342 and 131I-iodoHoechst 33258. The mobile phase, consisting of methanol and aqueous ammonia (0.2%) in the ratio 2:3, resolved and separated the radiochemical from unlabeled ligand and other reagents used in the reaction, thereby resulting in high radiochemical purity and yield. The iodinated Hoechst 33258 did not show any selective binding to nuclear DNA when cell fractionation studies were performed with cultured mammalian cells as well as in mice testes. Fluorescence microscopy studies with V79 cells stained with these dyes, showed the superiority of Hoechst 33342 in selective localization in nuclear DNA compared to Hoechst 33258. The difference in behavior of these two dyes in terms of binding to nuclear DNA, and hence their ability to provide protection against damage caused by ionizing radiation, may be explained on the basis of the molecular charge. The high chemotoxicity of Hoechst 33342 observed in the present studies suggests that its usefulness as a radioprotector against chronic irradiation of tissue by incorporated radionuclides may be limited.

Animals↗
PubMed1994

Dosimetry of Auger-electron-emitting radionuclides: report no. 3 of AAPM Nuclear Medicine Task Group No. 6.

The biological effects of Auger-electron-emitting radionuclides can be as severe as those of alpha particles of high linear energy transfer. A great deal of effort has been expended in exploring the biological effects of Auger electron emitters. Much of this effort has been devoted to improving theoretical and experimental techniques required to calculate absorbed doses and correlate them with the observed biological effects. Given that the main purpose of dosimetry is to obtain a physical descriptor with which to correlate radiation toxicity, then nowhere is this challenge greater than when biological specimens are subject to Auger electron cascades. The dense shower of short-range Auger electrons released by radionuclides, which decay by electron capture or internal conversion, results in biological damage that is highly dependent on the location of the decay site within the cell. In this report, different approaches to Auger electron dosimetry are described and compared. Methods to calculate the absorbed dose from Auger electron emitters at the DNA, cellular, multicellular, and organ levels are described as they relate to the biological effects. The concept of a radiation weighting factor for Auger electrons to be used in the calculation of equivalent dose is reviewed. The importance of subcellular distribution of Auger emitters in determining the biological effects of these radionuclides is emphasized and incorporated into the equivalent dose formalism. The Task Group recommends that a preliminary radiation weighting factor of 10 be used for deterministic effects of Auger electrons, and a value of 20 for stochastic effects.

Biophysical Phenomena↗
PubMed1994

Relative biological effectiveness of 99mTc radiopharmaceuticals.

The radiotoxicity of three 99mTc-labeled compounds is investigated using spermatogenesis in mouse testis as the experimental model, and spermatogonial cell survival as the biological end point. The radiopharmaceuticals studied are pertechnetate (99mTcO4-), pyrophosphate (99mTc-PYP), and hydroxyethylene diphosphate (99mTc-HDP). The mean lethal doses at 37% survival (D37) are 0.70 +/- 0.06, 0.84 +/- 0.13, and 0.59 +/- 0.08 Gy for 99mTcO4-, 99mTc-PYP, and 99mTc-HDP, respectively. When these results are compared with the D37 value obtained with external x rays or internal gamma rays, the relative biological effectiveness (RBE) of these compounds are 0.94 +/- 0.09, 0.79 +/- 0.13, and 1.1 +/- 0.16, respectively. These results show that the radiotoxicity of 99mTc in mouse testis is essentially similar to that of low-LET radiations (i.e., RBE approximately 1). To understand these results, the distribution of these radiocompounds in the testis is determined and correlated with the observed RBE values. The expected range of RBE values for 99mTc radiopharmaceuticals in organs is 0.95 to 1.5, depending on the fraction of organ activity that is bound to DNA. This suggests that the Auger electrons emitted in the decay of 99mTc are not capable of causing extreme toxicity in vivo. These results provide further support for 99mTc as the radionuclide of choice for imaging in nuclear medicine.

Animals↗
PubMed1994

Radiotoxicity of platinum-195m-labeled trans-platinum (II) in mammalian cells.

The chemotoxicity and radiotoxicity of trans-dichlorodiammineplatinum (II) labeled with 195mPt (trans-195mPt) are investigated to ascertain the potential of radioplatinum coordination complexes as antineoplastic agents. Platinum-195m, with a half-life of about 4 days, is a prolific emitter of low-energy Auger electrons because of the high probability of internal conversion in its isomeric transitions. The kinetics of cellular uptake and retention after incubation and the radiotoxicity of this Auger electron emitter in the form of trans-195mPt is investigated using cells of the Chinese hamster V79 cell line. The cellular uptake of 195mPt reaches a plateau in about 3 to 5 h of incubation and varies nonlinearly with the extracellular concentration of radioactivity. The radioactivity is eliminated from the cells after incubation with an effective half-life of 24 h. Cell survival data, when corrected for the chemical toxicity of nonradiolabeled trans-platinum, give a cell survival curve typical for radiations with high linear energy transfer. At 37% survival, the mean lethal cellular uptake is about 1.0 mBq/cell. Dosimetric considerations, based on subcellular distribution of the radionuclide, yield a value of 4.8 for the relative biological effectiveness when compared with 250 kVp X rays. Theoretical Monte Carlo track-structure calculations indicate that the density of radical species produced in liquid water in the immediate vicinity of a 195mPt decay site is substantially greater than the density of species along the track of a 5.3 MeV alpha particle. This explains qualitatively the efficacy of 195mPt in causing high-LET radiation type biological effects. The extreme radiotoxicity of intranuclearly localized 195mPt, in conjunction with the proclivity of platinum chemotherapy agents to bind to DNA in the cell nucleus, suggests that the combination of chemical effects and the effects of Auger electrons that can be obtained with radioplatinum coordination complexes may have potential in the treatment of cancer.

Animals↗
PubMed1994

Biological effect of lead-212 localized in the nucleus of mammalian cells: role of recoil energy in the radiotoxicity of internal alpha-particle emitters.

The radiochemical dipyrrolidinedithiocarbamato-212Pb(II) [212Pb(PDC)2] is synthesized and its effects on colony formation in cultured Chinese hamster V79 cells are investigated. The cellular uptake, biological retention, subcellular distribution and cytotoxicity of the radiocompound are determined. The 212Pb is taken up quickly by the cells, reaching saturation levels in 1.25 h. When the cells are washed, the intracellular activity is retained with a biological half-life of 11.6 h. Gamma-ray spectroscopy indicates that the 212Pb daughters (212Bi, 212Po and 208Tl) are in secular equilibrium within the cell. About 72% of the cellular activity localizes in the cell nucleus, of which 35% is bound specifically to nuclear DNA. The mean cellular uptake required to achieve 37% survival is 0.35 mBq of 212Pb per cell, which delivers a dose of 1.0 Gy to the cell nucleus when the recoil energy of 212Bi and 212Po decays is ignored and 1.7 Gy when recoil is included. The corresponding RBE values compared to acute external 137Cs gamma rays at 37% survival are 4.0 and 2.3, respectively. The chemical Pb(PDC)2 is not chemotoxic at the concentrations used in this study. Because the beta-particle emitter 212Pb decays to the alpha-particle-emitting daughters 212Bi and 212Po, these studies provide information on the biological effects of alpha-particle decays that occur in the cell nucleus. Our earlier studies with cells of the same cell line using 210Po (emits 5.3 MeV alpha particle) localized predominantly in the cytoplasm resulted in an RBE of 6. These earlier results for 210Po, along with the present results for 212Pb, suggest that the recoil energy associated with the 212Bi and 212Po daughter nuclei plays little or no role in imparting biological damage to critical targets in the cell nucleus.

Alpha Particles↗
PubMed1994

Application of the linear-quadratic model to radioimmunotherapy: further support for the advantage of longer-lived radionuclides.

UNLABELLED: Radioimmunotherapy (RIT), as it is currently practiced, delivers low doses to tumors primarily because of dose-limiting bone marrow toxicity. The biologic effectiveness of RIT depends on the total dose, dose rate and the fractionation schedule of the radiolabeled antibodies administered. METHODS: An approach based on the linear-quadratic (LQ) model, which is currently used in conventional radiotherapy, is advanced for treatment planning in RIT. This approach incorporates repair rates, radiosensitivity of the tissues, biologic half-lives of the antibodies, physical half-lives of the radionuclides, dose rates and total doses needed for a given biologically effective dose. The concept of a relative advantage factor (RAF) is introduced to quantify the therapeutic gain that can be realized by using longer-lived radionuclides instead of the shorter-lived counterparts currently in use. RESULTS: RAFs are calculated for different biologic and physical half-lives, and values as high as 3 to 5 can be attained when longer-lived radionuclides are used. The RAFs predicted by the LQ model reaffirm the authors' earlier conclusion based on the time-dose-fractionation approach that relatively long-lived radionuclides coupled to monoclonal antibodies are indeed more likely to deliver therapeutically effective doses to tumors. Several radionuclides are evaluated in this context. CONCLUSION: The authors maintain that 32P is the most promising isotope and the optimal physical half-life is about two to three times the biologic clearance half-life of the antibodies in the tumor.

Brachytherapy↗
PubMed1994

Vitamins as radioprotectors in vivo. II. Protection by vitamin A and soybean oil against radiation damage caused by internal radionuclides.

Tissue-incorporated radionuclides impart radiation energy over extended periods of time depending on their effective half-lives. The capacity of vitamin A dissolved in soybean oil to protect against the biological effects caused by internal radionuclides is investigated. The radiochemicals examined are DNA-binding 125IdU, cytoplasmically localized H125IPDM and the alpha-particle emitter 210Po citrate. As in our previous studies, spermatogenesis in mice is used as the experimental model and spermatogonial cell survival is the biological end point. Surprisingly, soybean oil itself provides substantial and equal protection against the Auger effect of 125IdU, which is comparable to a high-LET radiation effect, as well as the low-LET effects of H125IPDM, the dose modification factors (DMFs) being 3.6 +/- 0.9 (SEM) and 3.4 +/- 0.9, respectively. The protection afforded by the oil against the effects of 5.3 MeV alpha particles emitted by 210Po is also significant (DMF = 2.2 +/- 0.4). The presence of vitamin A in the oil further enhanced the radioprotection against the effect of 125IdU (DMF = 4.8 +/- 1.3) and H125IPDM (DMF = 5.1 +/- 0.6); however, no enhancement is provided against the effects of alpha particles. These interesting results with soybean oil and vitamin A, together with data on the subcellular distribution of the protectors, provide clues regarding the mechanistic aspects of the protection. In addition, the data for vitamin A reaffirm our earlier conclusion that the mechanism by which DNA-bound Auger emitters impart biological damage is primarily indirect in nature.

Animals↗
PubMed1994

Multicellular dosimetry for micrometastases: dependence of self-dose versus cross-dose to cell nuclei on type and energy of radiation and subcellular distribution of radionuclides.

UNLABELLED: In radioimmunotherapy, the treatment of bulk tumors by radionuclides that emit energetic beta particles is the preferred approach. However, for the eradication of small clusters of cancer cells, radionuclides that emit Auger electrons or alpha particles are considered to be advantageous because of their ability to deposit radiation energy locally. If such radionuclides are internalized by the cells, the total dose to the cell nuclei is thought to be primarily determined by the self-dose (dose to cell nucleus from activity within the cell) in comparison to the cross-dose (dose to the cell nucleus from activity in all other cells). METHODS AND RESULTS: The self-dose-to-cross-dose ratios to the cell nucleus were calculated for different cluster sizes (26-400 microns) with monoenergetic electron and alpha particle sources distributed uniformly in different cell compartments (cell surface, cytoplasm, nucleus). Model calculations were also performed for several radionuclides (Auger, beta and alpha emitters). Absorbed fractions for sources of monoenergetic electron and alpha particles, distributed uniformly in small spheres (26-5000 microns), were also calculated along with S-values for a number of radionuclides. CONCLUSIONS: When most of the cells in the cluster are labeled with beta or alpha emitters, the cross-dose component of the total dose is important irrespective of cluster size and subcellular source distribution and increases as the cluster size increases. The self-dose is always important for Auger emitters. When the self-dose is negligible, the mean absorbed dose to the cell nuclei is well represented by the mean dose to the micrometastasis.

Alpha Particles↗