desoxyepothilone-b and Neoplasm-Metastasis

Standard cytotoxic chemotherapy of locally advanced or metastatic breast cancer includes the microtubule-stabilizing taxanes, but like other cytotoxic drugs their effectiveness is compromised by resistance that is either inherent or develops during treatment. Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to overcome taxane or multidrug resistance, based on potent preclinical antitumor activity against resistant tumor lines. Ixabepilone is the best-studied epothilone clinically and is active in patients with metastatic breast cancer that has been pretreated with, or had established resistance to, taxanes and/or anthracyclines. In a phase III trial in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer, adding ixabepilone to capecitabine significantly improved progression-free survival and the overall response rate compared with capecitabine alone. The primary toxicities associated with ixabepilone treatment are neuropathy and neutropenia, but both are generally manageable. Other epothilones currently in clinical studies are KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584, which have all shown activity in patients with pretreated or resistant metastatic breast cancer.

Topics: Breast Neoplasms; Capecitabine; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Epothilones; Female; Fluorouracil; Humans; Neoplasm Metastasis; Tubulin Modulators

Based on the pre-clinical spectrum of activity in taxane-resistant cell lines, we evaluated KOS-862 (epothilone D; 12,13-desoxyepothilone B) as second-line chemotherapy in androgen-independent prostate cancer.Thirty-eight men with metastatic androgen-independent prostate cancer and evidence of progression following docetaxel-based chemotherapy were treated with KOS-862, 100 mg/m(2) (maximum of 240 mg) i.v. weekly for 3 weeks, repeated every 4 weeks. The primary objective for this study was to determine the antitumor activity, measured by PSA decline by more then 50% confirmed 4 weeks later. Two patients (5.3%, 90% CI 1-16%) met criteria for confirmed PSA decline. While both of these patients had previously been treated with docetaxel, neither had confirmed docetaxel-refractory disease. None of the 24 patients with measurable disease had a confirmed partial response. Seventy-three percent of patients had an adverse event leading to dose delay, reduction, or treatment discontinuation. Neurological toxicity and fatigue predominated. Seventeen patients (44.7%) had treatment related grade 3 neurological adverse events including peripheral sensory neuropathy (n = 4, 10.5%), ataxia (n = 3, 7.9%), peripheral motor neuropathy (n = 1, 2.6%), involuntary muscle contractions (n = 1, 2.6%) and neuropathic pain (n = 1, 2.6%). One subject (2.6%) had a grade 4 treatment peripheral motor neuropathy. Further study of this dose and schedule of KOS-862 in this patient population cannot be recommended due to both lack of activity and excessive toxicity.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Epothilones; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids; Treatment Outcome

A convergent ring-closing metathesis strategy has been employed for the highly concise syntheses of 10,11-dehydro-13,14-[17]desoxyepothilone B ([17]ddEpoB) and 10,11-dehydro-14,15-[18]desoxyepothilone B ([18]ddEpoB), which are 17- and 18-membered ring homologues of 10,11-dehydro-12,13-desoxyepothilone B ([16]ddEpoB or epothilone 490). We have demonstrated that the ring-closing metathesis (RCM) provides [17]ddEpoB or [18]ddEpoB with a high level of stereocontrol in the generation of the desired olefin in the products. These analogues were evaluated for antitumor activity. The results from the in vitro assays revealed that the [17]ddEpoB analogue is highly active against various tumor cell lines with a potency comparable to that of [16]ddEpoB. This is the first example of a 17-membered ring macrolactone epothilone that has retained its antitumor activity. In contrast, the biological data revealed that [18]ddEpoB is significantly less active than either [17]ddEpoB or the parent [16]ddEpoB.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Epothilones; Humans; Inhibitory Concentration 50; Molecular Structure; Neoplasm Metastasis; Structure-Activity Relationship