Cytotoxicities unexpected

The cytotoxicity of taxoids 40-i and 40-S bearing the oxanorstatine residue were evaluated in our standard five human cancer cell line assay.71 As Table 7 shows, these two stereoisomers were found to possess considerably different cytotoxicity, which is rather unexpected. Taxoid 40-R showed a 3- to 10-fold increase in activity as compared to paclitaxel, while the other isomer, taxoid 40-S, exhibited a 2- to 4-fold decrease in activity, i.e. one to two orders of magnitude difference in activity is observed just by changing the stereochemistry of the epoxide moiety at C-3. This... 

Sometimes natural taxanes or synthetic taxoids exhibited unexpected cytotoxicities, which may provide new clues for SAR. Because m-azido baccatin 111 103 was found to be almost as comparably active as paclitaxel, 7-deoxy-9,10-O-acetylbac-catin 104 was prepared from taxinine 105, a plain and abundant inactive taxane from T. cuspidata. Both 104a and 104b were found to be inactive (IC50 at 10 M level). ... 

Mercuric chloride was not mutagenic in the Salmonella typhimurium plate incorporation assay (Wong 1988). These negative results are not unexpected because the Ames test is not suitable for the detection of heavy metal mutagens. Oberly et al. (1982) reported, however, that doses of mercuric chloride (4.4 and 5.9 g Hg/mL) approaching severely cytotoxic levels induced a weak mutagenic response in mouse lymphoma L5178Y cells but only in the presence of auxiliary metabolic activation. 

The consequences of pancytopenia include life-threatening anemia, spontaneous bleeding, and severely compromised host defense. Pancytopenia can be caused by direct toxicity to stem cells or bone marrow infrastructure myelophthisis (occupation of marrow by fibroplasia, osteosclerosis, neoplastic cells or other cells not normally found in the marrow) effects on mitosis, differentiation, or maturation or immune-mediated (antibody, cytotoxic T cell) destruction of stem cells. Any pancytopenia that is unexpected based on the mechanism of the test article warrants thorough investigation. 

Including this toxicity in the area of idiosyncratic toxicity is justified since the lung is not thought of a typical target for cytotoxic chemotherapy. Rather, the toxicity results from an unexpected organ differential that results in an unexpected but not rare toxicity. Further, there are few indicators that will provide insight into if and when this toxicity will be encountered. 

In 2006, Culcasi et al. (27A22) suggested that something in the MSS particulate phase reduced the cytotoxicity of MSS vapor-phase free radicals as there was an unexpected protective effect of particulate phase on the cytotoxicity of whole smoke compared to that of vapor phase of MSS alone. They concluded that the conventional smoke collection method, that is, separation of the smoke into vapor and particulate phases, distorted the true picture of free radical activity. In other words, free radical activity in cigarette smoke should... 

In 1978 the synthesis of the indenoisoquinoline NSC 314622 (Fig. 5.19) was reported as the result of an unexpected transformation during synthesis of nitidine chloride. Given its weak antitumour activity, it was not investigated further. Twenty years later, NSC 314622 resurfaced as a potential topoisomerase I (top 1) inhibitor and served as lead structure for the design of cytotoxic noncamptothecin topoisomerase I inhibitors such as the compound 19a . 

Curiously, the marked effect of AG 14361 on the antitumour effect of temozolomide on SW620 xenografts was not anticipated from the in vitro studies where AG 14361 had failed to potentiate temozolomide cytotoxicity in SW620 cells. One reason for this unexpected observation could be because of the vasoactive properties of AG 14361, as described above, potentially altering the microdistribution and delivery of chemotherapeutic agents. PARP-1... 

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