A weakly fungistatic concentration of miconazole in lag phase yeast cultures of Candida albicans antagonized development of phenotypic susceptibility to the direct fungicidal action of high-level (i.e. greater than 10(-5) M) miconazole. After development in the absence of drug, maintenance of susceptibility upon continued incubation was also antagonized by low levels of miconazole. This auto-antagonistic effect has important clinical implications.
We investigated whether preculture exposure to low-dose X-irradiation and culture treatment with 4-hydroperoxycyclophosphamide (4-HPCY), a synthetic derivative of cyclophosphamide (CY), might distinguish subtypes of thymic-dependent (T) lymphocytes that respond to specific antigen in vitro. Lymph node (LN) cells were obtained from mice pretreated with CY and immunized with aggregated (A) human IgG (HGG) in Freund's complete adjuvant (CFA), and proliferation was assessed by incorporation of tritiated thymidine. Primed LN cells were untreated or exposed to low-dose irradiation before being cultured in medium alone and in medium containing 4-HPCY. The results show that these agents (irradiation and 4-HPCY) distinguished, in a dose-dependent manner, subtypes of T-cells which contribute to the specific antigen-stimulated proliferative response in vitro. For LN T-cells and LN Lyt-1+ T-cells, 20-25 rads and 1.0 microM 4-HPCY inactivated non-overlapping cell subtypes that respectively accounted for 26% and 28% of the response to HGG. The remaining 46% of HGG-responding cells were not affected by either agent. Although similar cell subtypes were discerned in unseparated LN cells, it required use of higher agent-doses. Cell cycle analysis revealed that treatment with irradiation, 4-HPCY, and the combination (both agents) caused S-phase arrest of 29%, 30%, and 55% of HGG-responding cells, respectively. Thus, identification of these cell subtypes could not be attributed to agent-mediated inactivation of HGG-responding cells that might be in exclusively different phases of the cell cycle.
The present study examined the effect of pulse treatment with the in vitro active synthetic derivative of cyclophosphamide (CY), 4-hydroperoxycyclophosphamide (4-HPCY), and exposure to X-irradiation on the in vitro Concanavalin A (ConA), lipopolysaccharide (LPS), and antigen-specific blastogenic responses of in vivo-primed lymph node cells. Primed lymph node cells from CY-pretreated, aggregated (A) human IgG-complete Freund's adjuvant (AHGG-CFA)-immunized mice were untreated, exposed to various doses of irradiation, or pulse treated with different concentrations of 4-HPCY before being cultured in medium alone or in medium containing HGG, ConA, or LPS. The results show that HGG-responding and LPS-responding cells exhibited similar dose-inactivation profiles following exposure to irradiation or pulse treatment with 4-HPCY. More than 75% of reactivity was eliminated by exposure to 100 rads or pulse treatment with 20 microM 4-HPCY. In contrast to preculture pulse treatment with 4-HPCY, however, when primed lymph node cells were cultured in medium containing 4-HPCY (culture treatment) LPS-responding cells were shown to be more sensitive to inactivation than HGG-responding cells. The data further show that the effect of low-dose irradiation and of culture treatment with 4-HPCY on the HGG-specific response of primed lymph node cells was additive, suggesting that these agents inactivate different cell subtypes that contribute to the HGG-specific response in vitro.
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