PubMed · 9827503
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K Kasper. 1998. Long-range alpha detection.. https://pubmed.ncbi.nlm.nih.gov/9827503/
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Alpha-particle emitters are currently being evaluated for the treatment of metastatic disease. The dosimetry of alpha-particle emitters is a challenge, however, because the stochastic patterns of energy deposition within cellular targets must be taken into account. We propose a model for the tumor control probability of alpha-particle emitters which takes into account these stochastic effects. An expression for cell survival, which is a function of the microdosimetric single-event specific-energy distribution, is multiplied by the number of cells within the tumor cluster. Poisson statistics is used to model the probability of zero surviving cells within the cluster. Based on this analysis, a number of observations have been made: (1) The dose required to eradicate a tumor is nearly a linear function of the cell survival parameter z(0). (2) Cells with smaller nuclei will require more dose to achieve the same level of tumor control probability, relative to cells with larger nuclei, for an identical source-target configuration and cell sensitivity. (3) As the targeting of alpha-particle emitters becomes more specific, the dose required to achieve a given level of tumor control decreases. (4) Additional secondary effects include cell shape and the initial alpha-particle energy.
Mutation induction at the Hprt locus in Chinese hamster cells was studied after exposure to ultraviolet light, X-rays and alpha particles. While mutant frequency as a function of dose or fluence followed a linear-quadratic relationship with UV and X-rays, it showed a linear dependence for alpha particles. If mutant frequency is plotted vs. the logarithm of surviving fraction, a linear relationship is found in all cases although with different slopes. These are about equal with the two types of ionising radiations but about 10 times larger for UV. They can be used as a measure of mutagenic potential and are termed mutagenicity. It is shown that this parameter is correlated with the maximum of mutant yield, i.e., the number of mutants per cell at risk. It is concluded from this analysis that the maximum mutant yield is always found at doses or fluences which lead to 37% survival irrespective of the kind of radiation. If mutation induction is measured in X-irradiated cells after pre-exposure to UV, mutant frequency is higher than expected on the basis of independent action of the two radiations. Deletion spectra were determined by using multiplex polymerase chain reaction. It was found that the background of spontaneous mutants varied considerably and showed frequently repetitive patterns, presumably because of clonal expansion of pre-formed mutants. UV-induced mutants did not contain any deletions, while those with both X-rays and alpha particles the majority displayed partial and total deletions. Based on a total number of 134 X-ray- and 192 alpha-induced mutants, it is concluded that the total fraction of mutant clones without deletions (partial or total) is about 40% for X-rays and only about 20% for alpha-particles.
The mutagenicity of 4-methylnitrosamine-1-3-pyridyl-1-butanone (NNK), either alone or in combination with low dose alpha particle irradiation, was examined using the human-hamster hybrid (A(L)) cell assay. NNK induced a dose-dependent toxicity in A(L) cells. In combination with a 25 cGy dose of alpha particles, the induced survival fraction fell within the statistical range of the calculated values assuming an additive interaction of the two agents. In addition, NNK is mutagenic in A(L) cells at the CD59 locus. Furthermore, a low dose of NNK, when combined with radon alpha particles, resulted in a combined mutagenic effect in A(L) cells that was consistent with an additive model but less than additive at higher NNK concentrations. The majority of NNK induced CD59(-) mutants (77.6%) lost at least one additional marker in addition to the CD59 which encodes the cell surface antigen. When combined with alpha particles, the proportion of mutants with additional marker loss increased with increasing dose of NNK. Our study further confirms that NNK is mutagenic in mammalian cells, induces mostly deletions, and provides an in vitro assessment of the combined genotoxic effects of NNK and alpha particles at low environmentally relevant doses. This finding should be helpful in understanding the molecular mechanism of the mutagenic process as a result of multi-agent interaction.