Docetaxel cytotoxicities

The mechanism by which the cytotoxic agents were approved is of inferest. Many were approved on fhe basis of response rafe as a surrogafe for survival (e.g., via the accelerated approval path). - Of nofe is the development of fhe cytotoxic agents, capecitabine received initial accelerated approval on the basis of fhe surrogafe endpoint of response rate in patients with refractory breast cancer. This was later followed up with a randomized Phase 111 trial of docetaxel wifh or withouf capecifabine in patienfs with refractory breast cancer with this trial demonstrating an improvement in survival for the combination of docetaxel + capecitabine vs. docetaxel alone. ... 

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). 

As Table 2 shows, 3 -(2-methylpropyl)-taxoid 23a and the 3 -(2-methylprop-l-enyl)-taxoid 23d possess excellent activities comparable to that of docetaxel in both tubulin binding and cytotoxicity assays. It is also obvious that the activity is very sensitive to the bulkiness of the 3 -substituents as observed by the substantial decrease in activity with change of the C-3 moiety from 2-methylpropyl (23a) to the bulkier tran.y-2-phenylethenyI (23b) or 2,2-dimethylpropyl group (23c). 

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... 

The cytotoxicity of taxoids 46-55 were evaluated against our standard five human cancer cell lines. Results are summarized in Table 8 with the values for paclitaxel, docetaxel, and taxoid 24d (SB-T-1212) for comparison. 

As Table 8 shows, several of the new taxoids exhibit similar or enhanced activity as compared to paclitaxel and docetaxel. Taxoid 48 (SB-T-104221 nonataxel) with 2-methylprop- 1-enyl groups at both C-3 and C-2 is more active than both paclitaxel and docetaxel, clearly establishing that a benzoate group at C-2 is not necessary for strong cytotoxicity in lieu of the appropriate alkyl, alkenyl, or cyclohexyl group. Taxoids 49-51 bearing a combination of 2-methylprop-1-enyl and 2-methylpropyl groups at C-3 and C-2 were, however, all less potent than 48. The results clearly indicate the considerable sensitivity for the modification at these positions. Based... 

Cytotoxicity of 3 -CF3-taxoids 71 and 72a-h thus obtained were evaluated against human cancer cell lines and the results are summarized in Table ll.45 As Table 11 shows, all these taxoids possess excellent activities, and are substantially more potent than either paclitaxel or docetaxel in virtually every case. The most remarkable results are, however, one order of magnitude better activities of the 10-acylated taxoids 72a-h as compared to paclitaxel and docetaxel against the drug-resistant breast cancer cell line, MCF7-R. The marked difference in cytotoxicity observed between 3 -(2-CF3-ethyl) taxoid, 68 or 69, and 3 -CF3-taxoids 72 reconfirms high sensitivity of the C-3 position to the size of substituent for the biological activity. 

Taxine alkaloids are complex polycyclic compounds in which N is present but not as an integral part of a ring. The taxines are found in Taxus (yew) species (Taxaceae). Taxine A (C61 CIO ] C6-0-C0-CH(0H)-CH(N(CH3)2)-Phe) is substantially responsible for yew toxicity. The related polycyclic amide taxol (paclitaxel) and the closely related docetaxel are tubulin-binding, antimitotic cytotoxics that are used clinically as anticancer drugs. A variety of taxines have been isolated from Taxus species. 

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... 

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