Any significant change in the pharmacokinetics of an anticancer drug would have a bearing on its therapeutic efficacy and toxicity. Nutritional deficiencies have been shown to affect the pharmacokinetics of a drug. Since malnutrition and undernutrition are widely prevalent in India, the effect of initial nutritional status on the overall kinetics of methotrexate (MTX) administered to cancer patients appeared to be of practical importance. A study of 6 Indian children with malignancies was made to examine the pharmacokinetics of low dose MTX and its relationship to the nutritional status. The results indicate that the relative weight correlates well with the anthropometric parameters, nutritional parameters and dietary intake and may be used as a marker of nutritional status.
Several recent publications indicate that Ca2+ is required for protein synthesis in mammalian cells, including the Ehrlich ascites tumor cell. The present communication examines whether the effects of Ca2 + might be mediated through calmodulin or a related protein. Four calmodulin antagonists belonging to different chemical categories were used to provide evidence of calmodulin involvement. Three of the antagonists inhibited protein synthesis in intact cells; 50% inhibitory concentrations were 10 pM calmidazolium, 12 pM N-(6-aminohexyl)-5-chloro-lnaphthalenesulfonamide (W,) and 17.5 pM trifluoperazine (TFP). Initiation was preferentially inhibited as indicated by an increase in the 80s monomers accompanied by a significant disaggregation of polyribosomes. All the antagonists also inhibited protein synthesis initiation in the cell-free protein-synthesizing system; 50% inhibitory concentrations for compound 48/80, calmidazolium, TFP, and W7 were 10 pM, 125 pM, 300 pM and 500 pM, respectively. A weak analogue of W7 inhibited only 20% at 1000 pM. Inhibition in the cell-free system was reversed by the addition of exogenous calmodulin in all four cases. The levels of 43s complexes were significantly elevated with all four antagonists, indicating a block in the utilization of 43s complexes.The similarity of the effects of four distinct classes of antagonists and their ready reversal by exogenous calmodulin leads us to suggest that there may be a role for calmodulin or a very similar calcium-binding protein in protein synthesis.Calmodulin (CaM), the ubiquitous calcium-binding regulatory protein, is considered to play a pivotal role in eukaryotic cells [l]. It is a member of a family of calcium-binding proteins with similar physical, chemical and sometimes functional properties [2]. CaM has four binding sites for calcium ions and, upon calcium binding, undergoes a large conformational change, exposing a hydrophobic region. Through this hydrophobic region CaM interacts with other proteins and exerts its regulatory effects, conferring calcium sensitivity on a multitude of enzyme systems and cell functions [3].Calmodulin levels increase during periods of cell growth and differentiation [4 -61. Small (2 -3-fold) increases in calmodulin content of transformed cells have been reported [6 -81. This and other indirect evidence has stimulated interest in the possibility that CaM may be involved in regulating cell growth and transformation, but this attractive hypothesis is still speculative.Brostrom and co-workers have shown that depletion of cellular calcium causes a marked inhibition of protein synthesis in a wide variety of cell types [9]. Our earlier data demonstrate an inhibition of protein synthesis in Ehrlich cellsCorrespondence to E. C. Henshaw, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, New York 14642, USA Abbreviations. CaM, calmodulin; W,, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; W5, N-(6-aminohexyl)-naphthalenesulfonamide; TFP, trifluoperazine; Me2S0, dimethyl sulfoxide;...
Abstract. Protein synthesis in Ehrlich ascites tumor cells is inhibited when cellular calcium is depleted by the addition of EGTA to the growth medium. This inhibition is at the level of polypeptide chain initiation as evidenced by a disaggregation of polyribosomes accompanied by a significant elevation in 80-S monomers. To identify direct effects of calcium on the protein synthesis apparatus we have developed a calcium-dependent, cell-free protein-synthesizing system from the Ehrlich cells by using 1,2-bis (Oaminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA), a recently developed chelator with a high (>10 s) selectivity for calcium (pKa = 6.97)over magnesium (pKa = 1.77). BAPTA inhibits protein synthesis by 70% at 1 mM and 90% at 2 mM. This effect was reversed by calcium but not by other cations tested. The levels of 43-S complexes (i.e., 40-S subunits containing bound methionyl-tRNAf, elF-2-GTP) were significantly lower in the calciumdeprived incubations, indicating either inhibition of the rate of formation or decreased stability of 43-S complexes. Analysis of 43-S complexes on CsCI gradients showed that in BAPTA-treated lysates, 40-S subunits containing elF-3, completely disappeared and the residual methionyl-tRNA-containing complexes were bound to 40-S subunits lacking elF-3. Our results demonstrate a direct involvement of Ca 2÷ in protein synthesis and we have localized the effect of calcium deprivation to decreased binding of elF-2 and elF-3 to 40-S subunits. p ROTEIN synthesis is a tightly regulated metabolic function in eukaryotic cells and is modulated in response to suboptimal nutrient conditions (13,17,21,22,39), which pose a direct stress on the cell, and in response to hormonal signals, which reflect the needs of the total organism (5, 20). We have studied the mechanisms whereby protein synthesis is inhibited in Ehrlich ascites tumor cells as a part of the cellular adaptation to several suboptimal growth conditions, including deprivation of glucose or an essential amino acid, and elevated temperatures. In these cases, inhibition has been localized to a reaction in polypeptide chain initiation (24, 39), but the intracellular effectors linking inhibition of initiation with altered nutrient supply remain unknown. In the present report we describe investigations of the mechanisms by which deprivation of another nutrient, calcium, inhibits protein synthesis in the Ehrlich cell and the cell-free system derived from Ehrlich cells. Calcium deprivation may offer new insights into regulation because calcium is not only a nutrient but also an intracellular effector mediating some of the actions of hormones, such as the polypeptide growth factors (6, 11,28,30), which affect the rate of cellular protein synthesis and cell growth (5,20). Facets of the calcium-dependent hormonal responses and calcium deprivation response may occur by the same pathway, so that elucidation of the mechanism of response to calcium deprivation may throw light on the calcium-dependent hormonal mechanisms.Eukaryotic cells have s...
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