The physiologically active form of vitamin D3, 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3), induces differentiation of several types of myeloid leukaemia cells. The acquisition of monocyte-like phenotype is accompanied by slower progression through the cell cycle, and G1 block has been reported to be the basis of this effect. It is shown here that human promyelocytic leukaemia HL60 cells treated with analogues of vitamin D3 which are potent inducers of monocytic differentiation have an additional cell cycle block. Exposure to 10(-7) M 1,25(OH)2D3 or 1,25-(OH)2-16-ene-D3 resulted in monocytic differentiation and the expected G1 block evident at approximately 48 h in a rapidly differentiating variant of HL60 cells (HL60-G), and at 96 h in the more slowly differentiating HL60-240 cells. In addition, a G2+M block was noted at approximately 72 h in HL60-G and HL60-240 cells. Exposure to vitamin D3 analogues also markedly increased the number of dikaryons, suggesting that cytokinesis was impaired more than karyokinesis. Treatment with a third analogue 25-hydroxy-16,23-diene-D3 produced little differentiation and had minimal effects on the cell cycle parameters. These findings indicate that vitamin D3 analogues regulate cell proliferation by control of the transition of G1 and G2+M phases, reminiscent of the cdc2/CDK2 type of cell cycle control.
Differentiation of mammalian cells is accompanied by reduced rates of proliferation and an exit from the cell cycle. Human leukemic cells HL60 present a widely used model of neoplastic cell differentiation, and acquire the monocytic phenotype when exposed to analogs of vitamin D, (VD,). The maturation process is accompanied by two blocks in the cell cycle: an arrest in the Gl/Go phase, and a recently described G2 + M block. In this study we have analyzed the traverse of the cell cycle phases of the well-differentiating HL60-G cells exposed to one of ten analogs of VD,, and compared the cell cycle effects of each compound with its potency as a differentiation-inducing agent. We found that in general there was a good correlation between the effects of these compounds on the cell cycle and on differentiation, but the best cell cycle predictor of differentiation potency was the extent of accumulation of the cells in the G, compartment. All analogs induced a marked decrease in the mitotic index, and polynucleation of HL60 cells was produced, especially by compounds which were effective as inducers of differentiation. Time course studies showed that induction of differentiation was accompanied by a transient increase of the proportion of cells in the G2 + M compartment, but preceded the G, to S, and the G, compartment blocks. These studies indicate that complex changes in the cell cycle traverse accompany, but do not precede, the acquisition of the monocytic phenotype by HL60 cells.Arrest of neoplastic cell proliferation is the major goal of cancer chemotherapy. While this can be achieved by induction of cell death by cytotoxic drugs, an alternative approach, the induction of terminal cell differentiation, is instinctively more appealing. One apparent advantage of differentiation therapy is that compounds normally present in the body, such as cytokines, and derivatives of vitamins and hormones, can be used for this purpose. Examples include the retinoids and analogs of vitamin D (e.g. Sporn, et al.
Treatment of mammalian cells with 1,25-dihydroxyvitamin D3 (1,25D3) produces a G1 to S (G1/S) phase cell cycle block. In addition, it has been noted that a smaller proportion of cells accumulates in the G2/M compartment in 1,25D3-treated cultures. Since cyclins have a major influence on the regulation of cell cycle progression, we determined the expression of cyclins A and B as markers of the G2 phase and of cyclin E as the marker of G1/S transition. No increase in the steady-state levels of cyclin A or cyclin B mRNA was detected in the total cell population or in the cyclin B1 protein in the G2/M cell cycle compartment. In contrast, immunodetectable cyclin E protein was increased in cell cultures as a whole and specifically in the G2/M compartment cells. Determination of BrdU incorporation into DNA by flow cytometry showed marked inhibition of DNA replication in cells with DNA content higher than 4C, and autoradiography of 3H-TdR-pulsed cells showed that polynucleated cells did not replicate DNA after 96 h of treatment with 1,25D3 or analogs. Taken together, these experiments show that at least a portion of the G2/M compartment in 1,25D3-arrested cultures of HL60 cells represents G1 cells at a higher ploidy level, which are blocked from entering the high ploidy S phase.
This article summarizes the diagnostic features and treatment recommendations for cutaneous anthrax, exemplified by a case report of nontypical cutaneous anthrax. The treatment of choice is medical, with ciprofloxacin or doxycycline the preferred antibiotics. However, surgical biopsy may be used if the clinical setting and microbiologic examination of swabs are not diagnostically conclusive. Histopathologic findings explain the clinical observation that most cutaneous anthrax lesions heal without scar formation.
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