Cytotoxic concentration

CarbocycHc 2/3 -didehydro-2/3 -dideoxyguanosine [118353-05-2] (carbovk, CBV, 66), C H 2N502, synthesized in 1988 (177), is a promising candidate for the chemotherapy of AIDS. CBV inhibits HIV repHcation and HIV-induced cytopathic effects in a variety of human T-lymphoblastoid ceU lines at concentrations approximately two hundred- to four hundredfold below its cytotoxic concentrations (177). CBV is as effective as AZT and DDC in reducing the expression of vkal antigen in HIV-infected CEM ceUs (177). The antivkal potency and selectivity of carbovk is comparable to the anti-HIV-1 potency and selectivity of 2/3 -dideoxyadenosine (178). The exact mode of antivkal action of carbovk has not yet been elucidated, but may be the modulating effect of intraceUular nucleotides on 5 -nucleotidase activity (179). 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Fig. 20.10. Enhancement of doxorubicin cytotoxicity in LoVo-resistant cells by verapamil and analogues. (Adapted from Ref. [77]). The results are expressed as fold increase in cytotoxicity represented by the ratio of doxorubicin IC50 in the absence and presence of verapamil and analogues (solid bars). The verapamil concentrations used were the minimal cytotoxic concentrations (IC20)-The compounds used were verapamil (1) ...

Figure 4. A typical viability curve for HIV-infected cell in the presence of anti-HlVdrug. EC50 is 50% antiviral effective concentration. CC50 is 50% cytotoxic concentration.

Regarding posihve hndings, responses may be generated only at highly toxic/cytotoxic concentrations, and the presence or absence of a dose-response relahonship should be considered. 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

Hydrogen peroxide transformed mouse myeloid progenitor cells (FDC-Pl) from interleukin-3 dependence to factor independence, but only at cytotoxic concentrations (> 12/5 pmol/L). Such a transformation was not induced by non-specific insults to the cells, such as sodium fluoride or heat shock treatment. The transformed cells produced tumours when injected into pre-irradiated mice (Crawford Greenberger, 1991). Hydrogen peroxide (10 pmol/L) induced overexpression of the proto-oncogene c-jun in hamster tracheal epithelial (HTE) cells c-jun overexpression led to proliferation and increased growth rate, as well as increased anchorage-independence of HTE cells (Timblin et al., 1995). 

HIV infection in humans is now pandemic. As of January 2006, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on December 1, 1981, making it one of the most destructive pandemics in recorded history. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries. An alternative therapy to circumvent this problem is the use of polyanionic substances, which demonstrated a number of promising features as potential anti-HIV drug candidates. In this respect, various SPs (e.g., heparin, DS, dextrin sulfate, cyclo dextrin sulfate, curdlan sulfate, pentosan polysulfate, mannan sulfate, sulfoevernan, and fucoidan) and derivatives thereof (e.g., O-acylated heparin, polyacetal polysulfate, polyvinyl alcohol sulfate, and modified cyclo dextrin sulfates) have been found to inhibit HIV replication in vitro at concentrations that are up to 10 000-fold lower than the cytotoxic concentration [2,71]. 

To assess the cytotoxic profile of 1, the effect of different concentrations of decitabine on colony formation in the human cell lines MDA-MGB-231, Calu-6, and DU-145 were observed (Table 2). The CC50 (50% cytotoxic concentration) values of 1 for MDA-MB-231, Calu-6, and DU-145 were 50 ng/mL. 

Selection of the appropriate concentration is important. The concentration should be high enough but still physiological relevant. Care must be taken to avoid using cytotoxic concentrations. For the best results, the hepatocyte cultures should be near 100 % confluent during the entire treatment period. 

CC50 = 50% cytotoxic concentration, the drug concentration that inhibits cell growth by 50% in vitro. 

Safrole has been found to be a weak hepatocarcinogen, which is linked to the formation of safrole-DNA adducts. Safrole treatment will induce oxidative damage in rat hepatic tissue (331) and is a genotoxic carcinogen in rat liver in vivo (332). These cytogenetic effects may result from covalent DNA modification in the rat liver. The threshold cytotoxic concentration found for safrole is 0.10 mug/ml safrole (333). 

Lowest concentration at which complete destruction of cells occurred Not active at cytotoxic concentrations. 

Compounds 33,35 and 37 were tested starting from the maximum non-cytotoxic concentrations. 2nt= not tested... 

Certonardosides A-E (23-27), Fig. (9) are sulfated at C-3 of the xylopyranose unit attached to C-26 of the steroidal side chain, while certonardosides F-I (28a, 28b, 29a, 29b), Fig. (10) contain a sulfate group at C-6 (a) of the steroidal aglycone. The isolated compounds were evaluated for their antiviral activity against HIV, HSV, CoxB, EMCV and VSV viruses. Certonardosides A-J were inactive within the range of non cytotoxic concentrations. Only weak antiviral activity against HSV was observed in compounds 29a and 29b and the desulfated analog of 28b. 

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