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Chemical and biological consequences of the radioactive decay of iodine-125 in plasmid DNA.
Doubly labeled [U-14C, 5-125I]iododeoxycytidine (IdC) triphosphate was synthesized and incorporated enzymatically into defined positions of the plasmid pBR322. After storage under various conditions, the stable end products were analyzed using radio-GC, radio-HPLC, and electron microscopy. In addition, solutions of 14C-IdC-labeled DNA containing Na125I as an internal radiation source were studied to investigate the influence of internal radiolysis. Transmutation of the covalently bound 125I leads to complete destruction of the labeled nucleotide, giving rise to 14CO2 and 14CO as major products. Fragmentation of the pyrimidine base is independent of solvent and DNA configuration. Internal radiolysis caused by Na125I leads to only minor damage. Electron microscopy studies reveal that decay-induced double strand breaks (dsb) occur both at the site of decay and in areas as far as hundreds of base pairs apart from that site. Number and distribution of the breaks is strongly dependent on solvent and DNA configuration. A direct correlation exists between the extent of fragmentation of the nucleotide and the mean number of dsb.
Cell kinetics of GM-CFC in the steady state.
The kinetics of cell turnover for myeloid/monocyte cells that form colonies in agar (GM-CFC) were measured through the progressive increase in their sensitivity to 313-nm light during a period of cell labeling with BrdCyd. Two components of cell killing with distinctly separate labeling kinetics revealed both the presence of two generations within the GM-CFC compartment and the properties of the kinetics of the precursors of the GM-CFC. These precursors of the GM-CFC were not assayable in a routine GM-CFC assay when pregnant mouse uterus extract and mouse L-cell-conditioned medium were used to stimulate colony formation but were revealed by the labeling kinetics of the assayable GM-CFC. Further, these precursor cells appeared to enter the assayable GM-CFC population from a noncycling state. This was evidenced by the failure of the majority of these cells to incorporate BrdCyd during five days of infusion. The half-time for cell turnover within this precursor compartment was measured to be approximately 5.5 days. Further, these normally noncycling cells proliferated rapidly in response to endotoxin. High-proliferative-potential colony-forming cells (HPP-CFC) were tested as a candidate for this precursor population. The results of the determination of the kinetics for these cells showed that the HPP-CFC exist largely in a Go state, existing at an average rate of once every four days. The slow turnover time for these cells and their response to endotoxin challenge are consistent with a close relationship between the HPP-CFC and the Go pool of cells that is the direct precursor of the GM-CFC.
Experiences with iododeoxycytidine in the treatment of ocular herpes simplex infections.
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[Some current problems in laboratory diagnosis and treatment of conjunctival infections].
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Heritable fragile sites on human chromosomes. XI. Factors affecting expression of fragile sites at 10q25, 16q22, and 17p12.
The fragile sites at 10q25, 16q22, and 17p12 can all be induced in lymphocyte culture by BrdU or BrdC added 6-12 hrs prior to harvest. Without induction, fra(10)(q25) is rarely expressed spontaneously, whereas fra(16)(q22) is frequently expressed spontaneously. Fra(17)(p12) is frequently expressed spontaneously but is probably expressed only after induction in some individuals. Distamycin A, netropsin, and Hoechst 33258 induced high levels of expression of fra(16)(q22) and fra(17)(p12) but did not enhance expression of fra(10)(q25). The mechanisms of induction of fra(16)(q22) by BrdU and distamycin A appear to be different, since the time of induction by BrdU reaches a maximum about 12 hrs prior to harvest whereas induction by distamycin A requires much longer exposure. The fragile sites at 10q25 and 16q22 were both induced in fibroblast culture by BrdU. Fra(17)(p12) is accepted as a fragile site because preliminary studies show that it behaves similarly in lymphocyte culture to fra(16)(q22); however, there is only limited evidence for fragility at 17p12.
[Superficial herpetic keratitis: comparative double-blind treatment with iododeoxycytidine and acyclovir].
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[Antiviral agents and cicatrization of the corneal stroma].
Infection of the cornea due to herpes simplex virus continues to be a problem for ophthalmologists despite treatment of the disease with antiviral drugs. These drugs are known to produce some toxic effects and prolonged administration is sometimes necessary. Using tensile strength measurements to assess tissue repair, healing of a 5 mm perforating corneal stromal incision was measured after treatment with different antiviral drugs four times a day for eighteen postoperative days. Results suggest that 3% adenine arabinoside, 3% acycloguanosine, 1% trifluorothymidine, and 1% iododesoxycytidine ointments do not delay (p greater than 0.05) normal stromal healing.
Recovery of cells from induced, potentially lethal damage.
The recovery of mammalian cells after a variety of treatments is, in part, governed by the cells' ability to deal with repairable, but potentially lethal, lessions. Kinetics of such recovery show a T1/2 of 10-20 hours after ultraviolet (UV) irradiation and 1.5-2.5 hours after X-irradiation. Recovery after exposure to mechlorethamine and bleomycin (BLM) is similar to X-ray recovery; after methylmethane sulfonate, recovery has components similar to X-ray and UV recovery. The sequential treatments of cells with 43 degrees C hyperthermia and X-rays (or reverse order) modify both the immediate survival after treatments as well as the subsequent recovery kinetics. Very similar results are found after BLM and hyperthermia treatments, suggesting strongly that after exposure to that drug a real repair system is operative. However, although recovery after X-irradiation is similar in vitro and in vivo, after BLM the site of treatment and of recovery strongly influences the magnitude and kinetics of recovery.
[Antiviral agents and corneal epithelium cicatrisation: study in rabbits (author's transl)].
Five clinically-used antiviral drugs (3% adenine arabinoside ointment; 3% acycloguanosine ointment; 0.24% idoxuridine ointment; 1% trifluorothymidine drops) were compared with a control (petrolatum base) to determine their toxic effects on rabbit corneal epithelium after injury by iodine vapors: --Only trifluorothymidine significantly retarded healing of epithelial erosions. --Histopathologic examination after seven-day treatment showed that all five drugs, except vidarabine and to a lesser degree acycloguanosine, caused toxic changes in the regenerating epithelium.
Use of 5-BrdUrd/313 nm light technique for identification of cells in initial S-phase within GM-CFCc compartment.
Long-term, low-level, BrdUrd infusion identifies two subpopulations of GM-CFCc with quite dissimilar sensitivities to 313 nm light. The responses of these two GM-CFCc subpopulations to hydroxyurea indicate that both are rapidly proliferating at the time of the assay. However, the absolute UV-light sensitivity of the S-phase components and the effects of increasing BrdUrd concentration indicate that the two GM-CFCc subpopulations passed through the previous cell cycle at widely disparate rates. Further, those GM-CFCc originating from a parental cell with a slow turnover are associated with a lower buoyant density than those GM-CFCc that have been in rapid cycle for at least two generations. These results indicate that the resistance to 313 nm-light irradiation, shown by S-phase cells in the first cell cycle of the BrdUrd labeling, may provide evidence of the proliferative history of the cell being assayed.
[Sister chromatid exchanges under bromine incorporation into DNA cytosine nucleotides. II. Utilization of 3H-deoxycytidine as a DNA cytosine precursor].
The incorporation of 3H-deoxycytidine (3H-Cdr) in the presence of thymidine (Tdr) into cultured human blood lymphocytes has been studied. The analysis of the label in interphase nuclei as well as in chromosomes at metaphase was carried out. The labeling was much higher when 3H-Cdr (0.5 to 1.0 C/ml, 2--4 x 10(-5) mM) was added to the cultures simultaneously with Tdr (4 x 10(-1) mM). This observation is considered as an indication that in the presence of high doses of Tdr exogeneous Cdr is utilized to synthesize cytosine of DNA rather than thymidine. During the first hours after its addition, the bulk of 3H-Cdr is eliminated from the culture medium. At 12 hrs of the incubation, the medium seems to be free of the nucleoside as shown particularly from the single chromatid localization of the label in chromosomes of the second mitosis. The incorporation into lymphocytes of 3H-Tdr administered in the same dose under the same conditions was registered for the whole period of observation (24 hrs). The data obtained are discussed in relation to lymphocyte catabolism of exogeneous nucleosides.
Comparative cytostatic activity of different antiherpetic drugs against herpes simplex virus thymidine kinase gene-transfected tumor cells.
A series of selective antiherpetic compounds were found to exert pronounced cytostatic activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) thymidine kinase (TK) gene-transfected mammary carcinoma FM3A cells. Based on their potency and mechanism of cytostatic action, the antiherpetic compounds could be divided into two different classes. The first class encompasses (E)-5-(2-bromovinyl)-2'-deoxyuridine and structurally related analogues thereof [i.e., the cytosine derivative (E)-5-(2-bromovinyl)-2'-deoxycytidine and the 4'-thio derivative (E)-5-(2-bromovinyl)-2'-deoxy-4'-thiouridine]. These compounds are exquisitely cytostatic against FM3A/TK-/HSV-1 TK+ and FM3A/TK-/HSV-2 TK+ cells (50% inhibitory concentrations ranging from 0.047 to 0.001 microM) and inhibit tumor cell proliferation by inhibiting cellular thymidylate synthase. The second class consists of the acyclic guanosine derivatives penciclovir, buciclovir, and ganciclovir. These compounds are also more inhibitory to the HSV-1 TK or HSV-2 TK gene-transfected FM3A cells than to FM3A/0 or FM3A/TK- cells, but at concentrations that are higher than the concentrations at which the (E)-5-(2-bromovinyl)-2'-deoxyuridine derivatives proved to be inhibitory. These acyclic guanosine analogues appear to be targeted at the cellular DNA polymerase. From this study, (E)-5-(2-bromovinyl)-2'-deoxy-4'-thiouridine emerged as a promising candidate compound for the treatment of HSV-1 TK gene-transfected tumors in vivo, due to its metabolic stability (i.e., resistance to hydrolysis by thymidine phosphorylase).