Cross-resistance studies

Toxicity and cross-resistance study on Chinese hamster ovary cells 441... 

Cross resistance studies All of the edifenphos-resistant strains were tested for their cross-resistance to related and unrelated systemic and contact fungicides. The growth rate of both mutant and sensitive strains were compared and their values were estimated. The resistance level was expressed as Q value (ratio of EDjq of sensitive strain/ED5Q of mutant strains)(31). 

Many herbicides, lilce ureas and triazines of the serine family share a common substructure a sp carbon attached to a nitrogen with a free electron pair and a positive n-charge (2,18,28). Their QSARs show usually a dependence on electronic and lipophilicity parameters. Individual compounds, chemically different, displace each other from the membrane (14.29). This family looses inhibitory potency in tris-treated cbloroplast membranes (7,18). Cross resistance studies of chloroplasts in triazine/triazinone or DCHU tolerant plants and algae have indicated subfamilies (reviewed in 13,18). None of these mutants are tolerant to phenol-type inhibitors. 

Representative compounds believed to bind at the benzamide site on the basis of evidence from competitive binding or cross-resistance studies (discussed below) are shown in Fig. 16.1.3. Although these compounds differ from zoxamide in their relative toxicity toward different organisms, they appear to bind to the same domain on y -tubulin. Selective toxicity may be governed by structural differences between organisms in this domain. 

A unique feature of prothioconazole is that it shows equally good activity against both cereal eyespot species, OcuUmacula yallundae (= Tapesia yallundae = Pseudocercosporella herpotrichoides W-type) and O. acuformis = Tapesia acuformis = Pseudocercosporella herpotrichoides R-type) whereas all other triazoles used against eyespot control only O. yallundae effectively. Surprisingly, in cross resistance studies prothioconazole revealed a unique profile as far as no positive cross resistance to either triazole-resistant or to prochloraz-resistant isolates could be detected [94]. 

Although it became clear quite early during cross resistance studies that fenhexamid was the first representative of a new mode of action class, the exact biochemical target was unknown when the new botryticide was launched in 1998. Only in 2001 did the research group of Pierre Leroux at INRA Versailles identify fenhexamid as the first member of a new class of SBI fungicides [110]. 

A series of novel 4-phenoxyquinolines has been developed which show potent control of fungicide-sensitive and resistant strains of powdery mildew in grape and cereal crops. Protective, curative, and systemic activity has been observed for these materials, which also control other fungi. Strong activity in field studies has been noted and no crossresistance was encountered when fungicide-resistant strains of mildew were treated with these compounds, thereby suggesting a novel mode of action. The discovery, synthesis and structure-activity relationship of this novel class of fungicides are presented, as well as some data from field and cross-resistance studies. 

The disease control demonstrated by this lead quinoline was very encouraging, yet we felt that appropriate cross-resistance studies were dictated prior to chemical elaboration of this lead in order to determine whether this material was acting by a known mode of action. 

The excellent greenhouse activity and the promising results fi om the cross-resistance studies clearly indicated that this material represented a potentially exciting and apparently unexamined area for study. The next step in the development of these fungicides was to identify viable synthetic routes and initiate structure-activity relationship (SAR) studies. 

Thermal Oxidative Stability. ABS undergoes autoxidation and the kinetic features of the oxygen consumption reaction are consistent with an autocatalytic free-radical chain mechanism. Comparisons of the rate of oxidation of ABS with that of polybutadiene and styrene—acrylonitrile copolymer indicate that the polybutadiene component is significantly more sensitive to oxidation than the thermoplastic component (31—33). Oxidation of polybutadiene under these conditions results in embrittlement of the mbber because of cross-linking such embrittlement of the elastomer in ABS results in the loss of impact resistance. Studies have also indicated that oxidation causes detachment of the grafted styrene—acrylonitrile copolymer from the elastomer which contributes to impact deterioration (34). 

Vinorelbine, a microtubule interactive agent, also has shown impressive response rates in metastatic breast cancer.60 Vinorelbine was approved by the FDA in 1994 for the treatment of non-small cell lung cancer. It is not approved for breast cancer, but response rates to vinorelbine range from 30% to 50%, with an overall 5% complete response rate in phase I and phase II studies in patients with advanced breast cancer. Importantly, paclitaxel, docetaxel, and vinorelbine do not appear to be cross-resistant with anthracyclines, which are arguably considered first-line treatment of metastatic breast cancer. 

Since rifamycins are important drugs for the treatment of M. tuberculosis infection [36, 86, 87] the activity of rifaximin on and interference with this bacterium have been carefully studied. Indeed, a potential problem of the treatment with this antibiotic is represented by the possibility that even very low blood levels achieved by oral administration might be able to select mutants, cross-resistant to rifamycins [85], in patients treated for GI infections and harboring M. tuberculosis. 

Three studies have addressed the possibility of inducing cross-resistance to Mycobacterium tuberculosis during the use of rifaximin. In an experimental guinea pig model of M. tuberculosis, rifaximin was administered in an effort to induce resistance among M. tuberculosis strains of human origin. Not only did no resistance develop, crossresistance to rifampin also did not occur [17, 18]. In another approach, M. tuberculosis strains were subjected to subinhibitory concentrations of rifaximin. No induction of resistance or cross-resistance to rifampin occurred... 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

The avermectin natural products are pesticides possessing novel chemistry and mode of action. Cross-resistance has not been observed in laboratory or field studies with mites andinsects tolerant to commercially available organophosphate, carbamate, chlorinated hydrocarbon and pyrethroid pesticides. 

The theory is that the earlier the combination is administered the better the chance for the resistance to be overcome. Unfortunately, cross-resistance can occur (9,43,44). Several randomized studies have demonstrated that the combination of chemotherapy and radiation therapy improves overall survival compared to chemotherapy alone (Table 1 and 1A). 

Application of compounds of the type 126 has been shown to result in increased crop yields under certain conditions," and they have been used as adjuvants for plants." The development of resistance and cross-resistance by insects has been studied. ... 

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