Differentiated thyroid cancer: radioiodine following lobectomy - a clinical feasibility study.

The surgical management of differentiated thyroid cancer remains controversial. Total thyroidectomy has been associated with higher rates of post-operative morbidity than more conservative surgery, but radioiodine ablation of residual thyroid tissue is considered to be particularly difficult after lobectomy. The purpose of this retrospective study was to assess the feasibility of 131I ablation after lobectomy, compared with total thyroidectomy, in patients who had undergone surgery for differentiated thyroid carcinoma.

Autologous lymphocytes as vectors to target therapeutic radiation, using indium-114m, in patients with lymphoid cell malignancy.

Autologous lymphocytes provide a potential vector for the delivery of a cytotoxic agent in patients with lymphoid cell malignancy. This report describes a phase I-II study using autologous lymphocytes to target the radionuclide indium-114m ((114m)In) in patients with refractory chronic lymphocytic leukaemia or small lymphocytic non-Hodgkin's lymphoma. Nineteen patients, the majority of whom had been heavily pretreated with conventional chemotherapy and radiotherapy, received between 69 and 211 MBq (114m)In-labelled autologous lymphocytes.

Role of damage-sensing/processing genes in the radiation response of haemopoietic in vitro colony-forming cells.

Purpose: To characterize the role of various cellular damagesensing, processing and survival genes in the in-vitro radiosensitivity of haemopoietic colony-forming cells.

Materials And Methods: Bone marrow cells from a range of different gene-knockout mice were irradiated in vitro with graded radiation doses and assayed for colony-forming efficiency.

Results: Colony-forming efficiency in the nulls was often lower by up to threefold compared with the wild-types.

Bone marrow toxicity in mice treated with indium-114m-labelled blood cells.

Clinical trials with autologous indium-114m-labelled lymphocytes have revealed significant anti-tumour effects in chronic lymphocytic leukaemia patients with highly resistant disease. Substitution of the lymphocyte vector with heat-damaged red blood cells (HDRBC) may make this treatment more universally applicable and reduce the dose-limiting myelosuppression encountered with labelled lymphocytes. Therefore, the bone marrow localization and toxicities of indium-labelled lymphocytes or HDRBC have been investigated in BDFI mice.

Transgenerational effects of preconception paternal contamination with (55)Fe.

The conjecture that germline mutations induced by radiation exposure before conception may predispose subsequent offspring to cancer remains contentious. Previous experimental studies have shown that preconception paternal irradiation with (239)Pu induces perturbations in the hemopoietic systems of offspring and influences sensitivity to a secondary carcinogen. In the present study, male DBA2 mice were injected intravenously with the Auger electron emitter (55)Fe (4 kBq g(-1)) 18 or 84 days before mating with normal females.

Effect of bcl-2 deficiency on the radiation response of clonogenic cells in small and large intestine, bone marrow and testis.

Purpose: Overexpression of bcl-2 protects against radiation induced apoptosis in lymphohaematopoietic cell types in vivo, whilst bcl-2 deficiency radiosensitizes murine T-lymphocytes in vitro. However, there are few data regarding the influence of bcl-2 deficiency on the radiosensitivity of non-lymphoid cell types. The purpose of this study was to investigate the role of bcl-2 in the clonogenic radiation response of intestinal crypts, bone marrow progenitor cells and testicular stem cells.

Modification of murine adult haemopoiesis and response to methyl nitrosourea following exposure to radiation at different developmental stages.

Purpose: To investigate the hypothesis that the developmental phase at which an individual encounters radiation damage affects its long-term sensitivity to a subsequent tumourigenic insult.

Materials And Methods: Either the pregnant C57B16 mouse was exposed to 137Cs gamma-rays at 4 or 15 days post-conception (embryonic and foetal stages respectively) or BDF1 offspring were irradiated at 4 or 21 days of age (neonatal and juvenile stages). Offspring were either assayed for changes in bone marrow stem cells and committed progenitors at 6, 12 and 18 weeks of age, or injected with the chemical carcinogen methyl nitrosourea (MNU) at 10 weeks of age and monitored for onset of neoplasia.

Hemopoietic damage and induction of leukemia in offspring due to preconception paternal irradiation from incorporated plutonium-239.

Preconception paternal irradiation has been implicated in a localized excess of childhood leukemia and non-Hodgkin's lymphoma close to a nuclear reprocessing plant. Other epidemiological studies, however, threw doubt on the validity of this hypothesis. Experimental evidence implicating preconception paternal X rays in the development of lung and skin cancers has also been questioned.

Loss of atm radiosensitizes multiple p53 null tissues.

An unusual clinical finding in ataxia-telangiectasia, a human disorder caused by mutations in atm, is exquisite sensitivity to gamma irradiation. By contrast, homozygous deletion of p53 is marked by radiation resistance in certain tissue compartments. Previous studies (A.

Mutation studies in lacI transgenic mice after exposure to radiation or cyclophosphamide.

We have used the Big Blue lacI transgenic mouse reporter system to investigate mutation induction in the testes, spleen and liver after exposure to an internally incorporated radionuclide, 114mIn, whole body irradiation with 60Co gamma-rays and systemically administered cyclophosphamide. Spontaneous mutation frequencies were 6-17x10(-6). No statistically significant mutation induction was observed in testes or spleen at 35 days after exposure to any test agent, although mutation frequencies tended to be increased (by approximately 1.

Transferrin-dependent uptake and dosimetry of Auger-emitting diagnostic radionuclides in human spermatozoa.

Unlabelled: Localization of Auger-emitting radionuclides within spermatozoa could lead to the induction of transmissible genetic damage. We have quantified in vitro uptake of the widely used diagnostic Auger-emitters, (111)In and 99mTc, by ejaculated human spermatozoa and investigated the role of transferrin in their cellular localization. The resultant dose to sperm heads, including cellular dosimetry for Auger emissions, has been calculated for each radionuclide and compared with that achieved using conventional macrodosimetry.

Transferrin-mediated uptake of plutonium by spermatogenic tubules.

Using isolated rat seminiferous tubules as an in vitro model, we have found that 238Pu can cross the blood-tubule barrier and accumulate within tubules in a time dependent manner. Furthermore, similar to 59Fe, tubule 238Pu uptake was inhibited by the addition of excess transferrin, suggesting that plutonium may utilize the physiological iron-transferrin pathway to cross the blood-tubule barrier. However unlike 59Fe, 238Pu was only transiently associated with the tubules, suggesting differences in the intracellular processing of these radionuclides.

The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase.

The depletion of cellular iron can lead to the inhibition of ribonucleotide reductase, preventing new DNA synthesis and hence inhibiting cell proliferation. Electron paramagnetic resonance (EPR) spectroscopy has been used to examine simultaneously for the first time the relationship between chelation of intracellular iron and the rate of removal and regeneration of the tyrosyl radical of ribonucleotide reductase within intact human leukemia K562 cells. The different physiochemical characteristics of relatively hydrophobic low molecular weight bidentate hydroxypyridinone chelators and the higher molecular weight hexadentate ferrioxamine have been exploited to elucidate these interactions further.

Transferrin-mediated uptake of radionuclides by the testis.

Unlabelled: In an attempt to explain the deleterious effects of gonadal radionuclide localization, we examined the role of transferrin in testicular radionuclide uptake.

Methods: In vivo testicular uptake and retention of the transferrin binding radionuclides 114mIn-citrate and 59Fe-citrate were compared with that of the nontransferrin binding isotopes 137Cs-citrate and Na125I for 63 days postinjection. Isotope uptake mechanisms were investigated in vitro using isolated seminiferous tubules and Sertoli cell monolayers grown in bicameral culture chambers.

Testicular toxicity of the transferrin binding radionuclide 114mIn in adult and neonatal rats.

Adult (70 d) and neonatal (7 d) male rats were dosed (i.p.) with 37 MBq/kg (1 mCi/kg; approximately 1 microgram elemental indium/kg) 114mIn, a transferrin-binding radionuclide.

Spermatogenic and mutagenic damage after paternal exposure to systemic indium-114m.

The cytotoxic and mutagenic consequences of systemic administration of 114mIn have been examined. Adult male rats were dosed intraperitoneally with 14.8 or 3.

In vivo induction of O6-alkylguanine-DNA-alkyltransferase in response to indium-114m.

The effect of systemic administration of the radionuclide 114mIn on O6-alkylguanine-DNA-alkyltransferase (ATase) activity has been examined in rats. In response to 14.8 MBq/kg 114mIn injected intraperitoneally, hepatic ATase was induced maximally approximately fivefold at 7 days after injection, at which time the cumulative radiation dose to the liver was approximately 2 Gy.

Subcellular distribution of desferrioxamine and hydroxypyridin-4-one chelators in K562 cells affects chelation of intracellular iron pools.

The interactions of iron chelators with intracellular iron pools have been examined by measuring the subcellular distribution of radiolabelled desferrioxamine (DFO) and the orally active hydroxypyridinone (HPO) chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94), as well as the ability of these chelators to modify the subcellular distribution of 59Fe delivered by the receptor mediated endocytosis of transferrin. K562 cells were pulsed with 59Fe transferrin and challenged with DFO or CP94 (100 microM IBE) for 20 or 240 min and then subjected to subcellular fractionation. At 20 min there was a significant decrease (P < 0.

Contrasting interspecies efficacy and toxicology of 1,2-diethyl-3-hydroxypyridin-4-one, CP94, relates to differing metabolism of the iron chelating site.

In order to define a predictive animal model for the effects of hydroxypyridinone (HPO) iron chelators in humans, we have compared the 28 d oral efficacy and toxicology of the HPO, 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in rats and guinea-pigs and related the results to the contrasting metabolism of this compound in the two species. CP94 was highly effective at mobilizing liver iron in rats but showed toxicity at higher doses, whereas in the guinea-pig the compound lacked toxicity but was ineffective at mobilizing liver iron. These differences can be explained by the contrasting metabolism of the drug between the two species.

In vivo and in vitro effects of 3-hydroxypyridin-4-one chelators on murine hemopoiesis.

The effects of 3-hydroxypyridin-4-one (HPO) iron chelators and desferrioxamine (DFO) on murine hemopoiesis in vivo and in vitro have been compared in order to investigate the mechanism by which leucopenia in mice and granulocytopenia in man occurs with 1,2-,dimethyl-HPO (CP20). Administration of 60 doses of 200 mg/kg CP20 to Balb/c mice resulted in significant anemia, lymphopenia and granulocytopenia accompanied by bone marrow hypocellularity. DFO and CP94 (1,2,diethyl-HPO) at the same dose also caused lymphopenia but marrow cellularity was unaffected.

Cell cycle synchronization and growth inhibition by 3-hydroxypyridin-4-one iron chelators in leukemia cell lines.

The effect of bidentate 3-hydroxypyridin-4-one (HPO) iron chelators on cell cycle arrest with subsequent cycle synchronization has been compared with that of the hexadentate desferrioxamine (DFO) in K562 and Daudi cells. The relationships between chelator concentration and inhibition of growth, DNA synthesis and ribonucleotide reductase, and phase of cell cycle arrest have also been explored. HPOs and DFO arrest the cell cycle in a dose-dependent manner causing a blockade at the G1-S border after 24 h at concentrations above 30 microM iron-binding equivalents.

Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4-one iron chelators in overloaded and nonoverloaded mice.

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice.

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.