Docetaxel cytotoxic effect

Our laboratories were the first to use CEPH family cell lines to demonstrate that a significant genetic component contributed to susceptibility to the cytotoxic effects of cisplatin, 5-FU and docetaxel (17,18). Dolan et al. estimated the heritability for susceptibility to cisplatin-induced cytotoxicity to be approximately 0.47 therefore sensitivity to the C5dotoxic effects of cisplatin is under appreciable genetic influence. Linkage analysis was performed and the strongest signal (lod 2.16, empirical /7-value 0.0005) was found on chromosome 1 at 44 cM (18). 

Black cohosh 2. Caffeine 3. Evening primrose oil 4. Scutellaria baicalensis 5. Starflower (borage) 1. Docetaxel 2. Paditaxel 3. Doxorubicin 4. Tamoxifen 5. Cisplatin 6. Vinorelbine t cytotoxic properties Unknown mechanism (black cohosh). Caffeine t cytotoxic effects of cisplatin wogonin present in Scutellaria enhances etoposide-induced apoptosis. Gamolenic acid found in evening primrose oil and borage potentiated the in vitro toxicity of paditaxel and vinorelbine, attributed to an unsaturated fatty acid as modulators of tumour cell chemosensitivity Be aware and avoid concomitant use... 

A group of mitotic inhibitors (vinblastine, vincristine, and vinorelbine) exert their cytotoxic effects by binding to tubulin. This inhibits formation of microtubules, causing metaphase arrest. Their mechanism of action and metabolism are similar, but the antitumor spectrum, dose and clinical toxicities of vinblastine, vincristine, and vinorelbine are very different. Paclitaxel and docetaxel are also mitotic inhibitors. However, they differ from the vinca alkaloids by enhancing microtubule formation. As a result, a stable and nonfunctional microtubule is produced. 

Some evidence su ests ondansetron may modestly affect the pharmacokinetics of cyclophosphamide and cisplatin but it does not appear to affect those of carmustine. Ondansetron did not affect the in vitro activity of epirubicin, bleomycin, cisplatin or es-tramustine. Cisplatin and fluorouracil do not affect the pharmacokinetics of ondansetron. In in vitro studies granisetron potentiated the cytotoxic effects of epirubicin, had an additive effect on bleomycin and estramustine activity and appeared not to affect the metabolism of docetaxel and paclitaxel. 

The improved activity of 3 -alkyl and 3 -alkenyl taxoids described above clearly establishes the dispensability of aromatic character at the C-3 position. Next, we investigated the effects of C-2 modification on cytotoxicity by replacing the C-2 benzoate moiety with nonaromatic ester groups. Replacement of the 2-benzoate with simple alkyl and alkenyl esters in conjunction with modification at C-3 provides a series of novel taxoids devoid of all the aromatic groups of paclitaxel and docetaxel.44... 

DJ-927 (49), a 9-dihydro-7-deoxy docetaxel analog under its phase 1 clinical trial, was effective against various mmors, especially P-gP overexpressing MDR tumors in vivo. Additional investigation showed that it is not a P-gP substrate and its cytotoxicity is not influenced by P-gP modulators. Although the authors proposed that the effectiveness of DJ-927 may be partly from higher intracellular accumulation, its mechanism against MDR tumors should be addressed in the fumre. ... 

In mouse mammary tumor cells, treatment with black cohosh increased the cytotoxicity of doxorubicin and docetaxel and decreased the cytotoxicity of cisplatin, but did not alter the effects of radiation or 4-hydroperoxycyclophos-phamide (an analog of cyclophosphamide that is active in cell culture) (Rockwell et al. 2005). 

The compound tetrandrine had a synergistic effect on the cytotoxicity of the chemotherapeutic agents 5-fluoro-uracil, oxaliplatin, and docetaxel in two gastric cancer cell lines (Wei et al. 2007). 

Our rationale is partly that prostate cancer is currently the most common non-skin cancer in America. It is estimated that in 2008, there will be 186,000 new cases of prostate cancer and 28,000 men will succumb to the disease (Prostate Cancer Foundation, 2008). Depending upon the staging of the disease, current therapies include hormonal treatments, radiotherapy, and radical prostatectomy. Those patients who have experienced relapse after hormonal therapy, are oftentimes in an advanced stage of disease and are treated with cytotoxics as docetaxel and mitox-antrone along with bisphosphonates (in the case of metastases) and radiation in case pain palliation is necessary. Unfortunately, these therapies can have major impacts on quality of life issues as side effects to therapies can often be severe (i.e. impotence). Clearly, new therapies directed towards managing or arresting the disease are necessary. 

Modification at the C-2 position also exhibits interesting effects on the cytotoxicity. Compound 8c, which is an SB-T-3002 analog with the addition of a fluorine at the j ara-position of the C-2 benzoate, has weaker activity than that of docetaxel but similar to that of paclitaxel. Difluoro-paclitaxel 8e showed drastically weaker cytotoxicity. 2-(3,5-Difluorobenzoyl)taxoid 8f was one of the most active analogs, showing that substitution at the meto-position is tolerated very well. These results are consistent with other reports that substitution at the para-position of the C-2 benzoate (cyano, chloro, methoxy, and azido) significantly decreases the activity but w6 a-substitution enhances activity (23). 

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