Drug resistance interactions

Psychoses, when they occur, appear to be due to drug effect interacting with a vulnerable personality organization (Luisada 1978). Our experience has been that some adolescents with borderline personality disorders, as well as adolescents at risk of schizophrenic decompensation, may have this vulnerability. Although we do not have hard data to support the hypothesis that patients with PCP psychoses that are most resistant to treatment have the poorest long-term prognosis (Erard et al. 1980), our observations have been that persistence of symptoms of psychosis after the first 2 to 3 weeks of treatment often correlates with extended periods of impai rment. 

Seydel, J. K. Coats, E. A. Cordes, H. P. Weise, M., Drug membrane interactions and the importance for drug transport, distribution, accumulation, efficacy and resistance, Arch. Pharm. (Weinheim) 327, 601-610 (1994). 

Therapeutic failure may be the result of nonadherence to medication, development of drug resistance, intolerance to one or more medications, adverse drug-drug interactions, or pharmacokinetic-pharmacodynamic variability. 

Vincristine resistance has been studied in Chinese hamster ovary cell lines cells resistant to vincristine also are resistant to vinblastine and vindesine. Suggestions were made that, in cells with relatively low levels of drug resistance, at least two prominent mechanisms of resistance can occur (22). In the first instance, cellular resistance may be attributable to membrane alterations that are reversible, functionally, by treatment with verapamil. In the second, resistance has been postulated to be due to an altered sensitivity of tubulin to the effects of the drugs the primary basis for postulating an altered interaction with tubulin was that a subgroup of cells resistant to vincristine showed enhanced sensitivity to taxol, a drug that can stabilize microtubules. It should be emphasized that differential sensitivities of tubulins from different tumor cells to the effects of vincristine or vinblastine has been proposed as a basis for the susceptibilities of cells to the cytotoxic effects of such drugs (23). Differences have been described in the electrophoretic patterns for tubulins obtained from vin-... 

Fig. 3. Possible interactions between PKC and MDRl-mediated drug resistance. Activation of PKC might activate the drug efflux by phosphorylation of PGP (A), induce or activate proteins which modulate PGP (B, Castro et al., 1999), or induce the transcription and translation of MDRl-mRNA (C). Inhibitors of PKC might prevent phosphorylation of PGP leading to a decrease the drug efflux (D). inhibit the efflux of drugs by direct interaction with the drug binding site(s) or the ATP-binding sites of PGP (E), or prevent the expression of MDRl-mRNA (F)...

Dive C, Hickman, JA (1991) Drug-target interactions - only the first step in the commitment to a programmed cell-death. Br J Cancer 64 192-196 Doehmer J, Goeptar AR, Vermeulen NP (1993) Cytochromes P450 and drug resistance. Cytotechnology 12 357-366... 

The lymph node microenvironment represents a niche where CLL cells interact with different types of cells including monocyte-derived nurse-like cells (NLC), CD3+ CD4+ CD154+ T cells, mesenchymal stromal cells, dendritic cells, and endothelial cells (15). In addition to cell-cell interactions, CLL cells are also exposed to a variety of soluble factors such as antigens, cytokines, and chemokines (2). It is the combination of such signals that renders CLL cells less susceptible to chemotherapy and promotes clonal evolution and drug resistance. Thus, the role of the microenvironment needs to be carefully considered in order to develop novel and more effective therapies for CLL treatment (16). In particular, the efficacy of new drugs must be evaluated under experimental conditions that recapitulate (or at least partially mimic) the CLL microenvironment. 

Rohwer N, Cramer T (2011) Hypoxia-mediated drug resistance novel insights on the functional interaction of HIFs and ceU death pathways. Drug Resist Updat 14 191-201... 

A close-up view showing the relative locations of the commonly identified drug-resistance mutations for NRTIs (in dark-gray) and for NNRTIs (in light-gray) with respect to the bound DNA. Most of the NRTI-resistance mutations are not located at the putative dNTP-binding site, but are at positions to have potential interactions with the nucleic acid template-primer. Conversely, all the NNRTI-re si stance mutations are clustered around the NNIBP and have direct contacts with NNRTIs or have direct effect on... 

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