Mutational side effects

As mentioned earlier, cancerous mutations can occur as a result of oxidative damage to DNA caused by free radicals generated as a damaging side-effect... 

From pilot studies carried out in the clinic with the NNRTIs TIBO R82913 [75] and pyridinone L-697,661 [76], it appears that the compounds are well tolerated and do not cause toxic side effects. Most of the HIV-1 isolates obtained from the patients treated with TIBO R82913 appeared to be as sensitive to the compound as wild-type virus only two HIV-1 variants were isolated, showing a sensitivity that was reduced 20-fold or more than 100-fold, the latter being caused by a mutation (Tyr —> Leu) at position 188 of the RT [77]. In fact, the latter mutation was lost upon passaging the virus in vitro in cord blood lymphocytes. Following treatment of the patients with pyridinone L-697,661, drug-resistant HIV-1 variants appeared that contained mutations at the RT positions 103 (Lys —> Asn) and 181 (Tyr —> Cys) [76]. 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

All the anticancer drugs so far known are mutagenic. This means that they induce some mutations within the gene distributions on DNA, such mutations being responsible for delayed relapses in patients who were cured of their initial tumor. Thus, mutagenicity appears to be a very prejudicial side-effect for any therapeutical drug, at least when it reaches too a high level. 

B. Ritonavir is a potent inhibitor of CYP3A4, the enzyme that rapidly inactivates lopinavir. This combination includes a low dose of ritonavir that is not likely to cause serious side effects but instead inhibits lopinavir metabolism. Ritonavir and lopinavir are HIV protease inhibitors and do not affect reverse transcriptase. Lopinavir is almost completely eliminated by metabolism to inactive metabolites little is eliminated unchanged by the kidney. Lopinavir is not known to inhibit the ability of HIV to mutate. Lopinavir inhibits the enzyme HIV protease, not a structural protein. 

Gross E, Ullrich T, Seek K et al. Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5— fiuorouracil-related side effects. Hum Mutat 2003 22 49i. Saeki E1, Ito S, Futatsugi M et al. Role of dihydropyrimidine dehydrogenase activity in patients with esophageal cancer. Anticancer Res 2002 22 3789-3792. 

Since point mutations of the ras proto-oncogene are often found in cancer, a vaccine was made with mutated ras peptides mixed with Detox. In a phase I study, CD4+ proliferation and CD8+ cytotoxicity specific to the mutated peptide, were observed. The side effects were minimal and one patient showed a stabilisation of the disease [213],... 

Introduced mutations affecting drug metabolism allow the study of drug metabolism, biotransformation and eventual undesired toxic side effects. 

In mice with mutations in the a2A-receptor gene it was established that the a2A subtype mediates the analgesic and anesthesia-sparing effects of clonidine and dexmedetomidine, but unfortunately also the sedative and vasodepressor effects of these drugs (Lakhlani et al., 1997). Thus, it seems unlikely that new subtype-selective compounds will lack the major side-effects of the existing drugs. 

Perhaps it will be possible to counter the effects of an increase in environmental mutagens by lowering the spontaneous-mutation rate (which must be due in part to chemical influences) with exogenous chemicals. It is not likely that a pill that reduces the mutation rate and possibly reduces carcinogenesis as a byproduct and that has no adverse side effects will suddenly appear. But new research has led to much greater knowledge of what controls the rates of mutation. 

Retinoids, topical as well as systemic, have been tried in EHK but were often found to be irritating. Nonetheless some patients are improved by oral acitretin,39 but the dose must be kept low in order to avoid the epidermolytic side effect of the drug. If correctly used, topical tretinoin and tazarotene may also be effective in some patients with EHK (Figure 8.7). Interestingly, the response to retinoid therapy seems to be partially determined by which keratin gene (Kl, K2e, or K10) is mutated patients with K2e and K10 mutations have the best response probably because they tolerate a retinoid-induced down-regulation of K2e expression better than other patients.40 However the... 

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