Leukemias paclitaxel

While dEpoB performed similarly to paclitaxel in sensitive tumor xenografts (MX-1 human mammary and HT-29 colon tumor), clearly superior effects of dEpoB were observed against MDR tumors under these slow infusion conditions. Thus, dEpoB (6 h, Q2D, 30 mg/kg x 5 doses, i.v.) demonstrated a foil curative effect when administered to nude mice bearing the resistant human lymphoblastic T-cell leukemia,... 

Huang Y, Ibrado AM, Reed JC, et al. Co-expression of several molecular mechanisms of multidrug resistance and their significance for paclitaxel cytotoxicity in human AML HL-60 cells. Leukemia 1997 11(2) 253—257. 

Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay examining apoptosis in smooth muscle cells and HL60 leukemia cells treated with paclitaxel. Abbreviations HL60, human leukemia 60. PTX, paclitaxel SMC, smooth muscle cells Tunel, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling. Source From Ref. 49. 

However, this effect of paclitaxel was found to be dependent on the drug dose and cell type (49,50). A number of studies have demonstrated that paclitaxel has several biologic attributes that are critical to the cascade of events involved in preventing restenosis, Paclitaxel was shown to inhibit SMC proliferation over a broad concentration range (0.01 — 10,000 ng/mL) without causing cell death or apoptosis (49,51). A comparison of human coronary artery SMCs and HL60 leukemia cells showed that paclitaxel did not induce apoptosis in SMCs at concentrations as high as 10,000 ng/mL (Fig. 4) (49). 

Mucositis and stomatitis have been reported with paclitaxel. Mucositis is characterized by ulceration of the lips, pharynx, and oral cavity, occurring 3-7 days after paclitaxel treatment (1,13,14,17,24,26,29,33,36-38). Mucositis appears to be more common during treatment of acute leukemias rather than solid tumors, when doses above 390 mg/m are used (24). Severe mucositis occurred during second and third courses, suggesting a cumulative effect, and was more severe if treatment was given at 15 days or less after previous courses. Patients... 

AC, doxorubicin, cyclophosphamide BCIRG, Breast Cancer International Research Croup CALCB, Cancer and Leukemia Croup B FAC, fluorouracil, doxorubicin, cyclophosphamide NSABP, National Surgical Adjuvant Breast and Bowel Project Pac, paclitaxel TAC, docetaxel, doxorubicin, cyclophosphamide. 

Low levels (0.1-1 pg/mL) of resveratrol have been reported to enhance cell proliferation, whereas higher amounts (10-100 pg/mL) cause apoptosis in a vari-ety of tumor and endothelial cells, including JB6 epidermal cells, human promyeloctye leukemia HL-60 cells, THP-1 human monocytic leukemia cells, U937 human promonocytic cells, various colon cancer cell lines, human mammary cancer cell lines, and human prostate cancer cells [121-131]. In somewhat of a contrast to these studies, a very recent report indicated that resveratrol reduced paclitaxel-induced apoptosis in a human neuroblastoma cell line (SH-SY5Y) by blocking paclitaxel-induced phosphorylation of JNKs, Raf-1, and BcT2 [132]. Of particular interest is a recent study in which it was shown to induce apoptosis in leukemic human lymphocytes but, under similar conditions, had no effect on the survival... 

The name Taxol was assigned to the compound purified from T. brevifolia based on the fact that the molecule contained hydroxyl groups and had a taxane nucleus. Studies on the structure of Taxol involved ultraviolet, infrared, and mass spectrometry, with full details of the structure being presented by Wani et al. in 1971. The structure of Taxol (paclitaxel) is presented in Figure 31.1. Studies in the late 1960s indicated that Taxol had activity against L1210 and 1534 leukemia cells. Taxol was also shown to have activity... 

Taxanes are diterpene compounds containing a taxane skeleton. Paclitaxel, the first compound identified with a taxane ring, was isolated from the bark of the pacific yew, Taxus brevifolia in 1971. Subsequently, paclitaxel and tax-oid derivatives have been reported from the foliage and bark of several other species of Taxus, like T. wallichinan, T. baccata, T. canadensis, T. cuspidata, and T. Yunnanensis In addition to the plant resources, some endophytic fungi, such as Tubercularia sp., Sporormia minima and Seimatoantlerium tepui-ense, have also been reported to produce paclitaxel and other taxoids. " Paclitaxel is effective for the treatment of leukemia and cancers. It has been reported that paclitaxel is capable of curing approximately 30%, 50%, and 20% of ovarian, breast, and lung cancer patients, respectively. ... 

Plant extracts are continuously being tested for bioactivity, and in cancer research, major enterprises for screens of antiproliferative activity are sometimes carried out. In one of these screens, nearly 70,000 species of terrestrial plants were tested against leukemia cell lines [95]. The authors labeled plant genera as hot if they yielded three or more plant species that showed activity in the screens. Six Psychotria species gave active extracts, so Psychotria earned the title of hot genus [95], This type of approach, extensive analysis of plant extracts in the search of bioactive phytochemicals, is very expensive, time-consuming, and labor-intensive, but can unveil precious new drug leads, as was the case with paclitaxel [96]. 

Studies in mice using the murine P388 leukemia sub-line selected for mdrl overexpression and the human colon cancer cell lines that express mdrl (Table 3B) suggest that intracellular pachtaxel derived from breakdown of CT-2103 is less subject to the multidmg resistance pump than is paclitaxel that enters the cell by diffusion of free pachtaxeP. As has been shown for other polymeric dmg conjugates, this is probably due active uptake of the conjugate by tumour cells with breakdown of the PG backbone and release of free paclitaxel at sites distant from the plasma membrane where they cannot be exported by intrinsic plasma membrane pumps. 

Paclitaxel has also been investigated in the treatment of other carcinomas, including melanomas, head and neck cancers, and leukemia. 

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