epothilone-a and Colorectal-Neoplasms

Physicians and patients alike have been heartened by the recent advances in the treatment of colorectal cancer. The emergence of novel agents that are active in the treatment of this devastating disease, such as cetuximab and bevacizumab, has been particularly notable. However, even before these recent events, a substantial change in prognosis for patients with metastatic colorectal cancer had occurred as a result of advances in traditional chemotherapeutic agents. Refinements in dose, schedule, and sequence continue to be made that could lead to further improvements in outcomes. Additionally, new chemotherapeutic agents with promise for activity in colorectal cancer are being studied. Chemotherapy is likely to remain a central element of the treatment strategy. Our understanding of its current role is discussed in this article.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Epothilones; Fluorouracil; Glutamates; Guanine; Humans; Indoles; Organoplatinum Compounds; Oxaliplatin; Pemetrexed

EPO906 (epothilone B) is a potent member of a new class of microtubule-stabilizing cytotoxic agents known as epothilones. Although structurally unrelated to the clinically validated taxanes, EPO906 acts similarly to promote the formation and stabilization of microtubules, arresting proliferating cells in mitosis, and eventually causing cell demise by apoptosis. In preclinical studies, EPO906 has shown anticancer activity both in vitro and in vivo against several cancer types, including models that are paclitaxel-resistant. Importantly, in contrast to the taxanes, EPO906 retained activity against cancer cells either overexpressing the P-glycoprotein efflux pump or bearing tubulin mutations. Two phase I studies with EPO906 were conducted to determine the safety and maximal tolerated dose on two different dosing schedules: weekly and every 3 weeks. Diarrhea was the dose-limiting toxicity on both schedules. Tumor responses were seen in colorectal cancer as well as a variety of other tumor types, such as breast, ovarian, lung, and carcinoid in these two phase I trials. Based on the promising results from phase I studies, phase II studies in numerous indications are ongoing.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Epothilones; Humans; Microtubules

Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer.. Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m(2) IV every 3 weeks) in combination with dexamethasone or prednisolone.. The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3-5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 %-36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3-2.9) and median overall survival was 6.1 months (95 % CI 3.7-8.4).. Patupilone given at a dose of 8 mg/m(2) IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer.

Topics: Adult; Aged; Antineoplastic Agents; Colorectal Neoplasms; Diarrhea; Epothilones; Female; Humans; Lethargy; Male; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Tubulin Modulators

The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan-5-fluorouracil-leucovorin (IFL).. Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status < or =1; peripheral neuropathy grade < or =1; and adequate laboratory parameters. BMS-247550 40 mg/m(2) was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks.. Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%).. Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Disease Progression; Epothilones; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Failure

Utidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Death; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Epothilones; Humans; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mice, Nude; Paclitaxel; Reactive Oxygen Species