EPOTHILONES

8/2/2019 EPOTHILONES

1/5

EPOTHILONES

Chemical compounds which affects the microtubules by increasing their cytotoxic effects. The

stops the cell division at G2 or M phase by attaching themselves to B tubulin. (Lee A Y et al,

2005). Even though it has same mechanism of action like Taxane but in clinical trials the drug

seem tto have less number of adverse effects on the health and better efficacy than the Taxane.

(Rosenberg et al, 2005).

MECHANISM OF ACTION

The main target is to inhibit the function of Microtubule.(Goodwin et al, 2004). Because the

microtubules are required for the proper cell division process, when they are inhibited the cell

division process doesnt occur in a normal way thus it hampers the division of cells. The effects

of epothilone is almost same as placitaxel as the way it binds to microtubule and the site of

binding is same as that of the placitaxel thus producing same set of effects in both in vitro as well

as in cell cultures. The binding site is the alpha tubulin site which forms a hetero dimer. When

this compound binds to that subunit then it decreases its dissociation rate thus enhancing the

stability of the microtubule. Tubulin polymerization also occurs inside the microtubule without

the presence of GTP, thus it leads to the arrest of the cell cycle at G2-M phase transition and

eventually leads to the cell apoptosis and death.(Balog et al, 1996). Since the microtubule

dynamics are suppressed the functions of the spindles are impaired. But current research also

shows that the concentrations at which spindle impairment is required for stopping the mitosis

doesnt occur by this epothilone. (Jordan et al, 2004).

CLINICAL TRIALS

Currently many epothilone analogues are under the clinical trial so that they can be used in

different forms of cancer. One of them which became a hot topic is Ixabepilone , that was

approved by the USA Food and Drug Administration in October 2007, which can be used inadvanced stages of Metastatic Breast cancer which is not possible to remove by the current

available chemotherapies.

In several clinical trials conducted it was found that Epothilone B has substantial anticancer

properties and that can be advised or can be taken in controlled dose which has been seen in the


2/5

xenograft models of humans. This result persuaded the Pharma companies to try different

analogues of epothilone, so currently many analogues are in trial phase of which some are

mentioned below.

(patupilone [EPO906] and sagopilone[SH-Y03757A, ZK-EPO, chemical structure] - Phase II

trial.

BMS-310705 and BMS-247550- Phase I trial

A phase III trial which has been conducted with Ixabepilone along with Capecitabine has already

been known to the medical world.

WHY IXABEPILONE?

Ixabepilone which is more metabolically stable is a semi synthetic analogue of epothilone B

compound that was developed only to get over the narrow therapeutic index of Epothilone. The

reason behind its increased metabolic stability is the replacement of lactone with lactam which

reduces its metabolism by carboxyeastrase. (Wartmann and Altmann, 2002). It is now studied in

phase III study ECOG2103 as first line of therapy for breast cancer along with carboplatin and

Trastuzumab. Experimental as well as clinical trials have shown that they are active in Taxane

nave cells thus can be used upon Taxane failure; these compounds are also capable of

maintaining their activity in those cells where MDR genes are expressed which were responsible

for Taxane resistance. Patients were with one dose of Ixabepilone and the result were quite

inspiring as only 43% got partial response who were Taxane nave and patients who were

already treated with Taxane and showed a SD of 38% showed 22% of effectiveness.(Lee A Y et

al, 2005).

IXABEPILONE CLINICAL TRIAL.

The treatment with Ixabepilone is considered to be monotherapy for the breast cancer where the

other drugs such as Taxane, anthracyclines and capacitabine were resistant. The clinical trial

conducted is a randomized control trial where 752 patients having metastatic breast cancers were

evaluated by giving them Ixabepilone (40 mg/m2 IV) along with Capecitabine, dosage were once

for every three weeks and were compared with those who were given only Capecitabine. The

patients who participated in the trial have been administered with Taxane and Anthracyclines but
http://en.wikipedia.org/w/index.php?title=Patupilone&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Sagopilone&action=edit&redlink=1http://commons.wikimedia.org/wiki/Image:Sagopilone_structure.svghttp://commons.wikimedia.org/wiki/Image:Sagopilone_structure.svghttp://en.wikipedia.org/w/index.php?title=Sagopilone&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Patupilone&action=edit&redlink=1


3/5

they are seemed to be resistant to these drugs. Those patients who were administered with

combined medications, there PFS( progression free survival) was found to be very good and

statistically significant. The PFS rate was 5.7 months for the combined dose and 4.1 for the

Capecitabine alone. (ASCO, 2007).

In the later stage, the Ixabepilone was administered to 127 patients in a single manner where the

dose was maintained as per the dose that was maintained in the combine trial. The patients

participating in this trial have already undergone treatments with Taxane, anthracyclines and

Capecitabine alone and arte found to be resistant to these ones as they are in metastatic breast

cancer stage. The independent review of radiology showed that the objective response rate was

found out to be 12.4 percent while same was 18.3 when it was based on the investigator

assessment. The response for medial rate was found out to be 6.0 months.

Those patients who were treated with Ixabepilone alone were found to be suffering from

peripheral neuropathy, and the number of patients falling prey to this is at 65 percent. Those who

were treated with combined drug of Ixabepilone and Capecitabine were found to be suffering

from Grade 3 or 4 pheripheral neuropathy and there percentage is found to be 23 percent. But no

such peripheral neuropathies were seen in those who were treated with Capecitabine alone.

When Ixabepilone was administered along with Capecitabine, then the incidence of grade 3 or 4

neutropenia was found in 68 percent of patients, while it was at 11 percent when Capecitabine is

given alone. 12 patients died of neutropenia who were administered combination of drugs. The

patients who died of neutropenia during this trial were found to have severe hepatic impairment

or baseline impairment after they are administered both the drugs in combination. So it was

concluded that this combination should not be used in those who have severe impairment in there

hepatic system. The persons who were given only Ixabepilone treatment they also developed

neutropenia and there percentage is 54%. (ASCO, 2007)

There are other side effects which were seen during this trial that accounts for less than 20%,

they are leucopenia, Anemia, thrombocytopenia, Arthralgia/mylagia, asthenia/fatigue, nausea,

alopecia, vomiting, diarrhea, mucostitis/stomastitis, and musculo skeletal pain. There are also

some side effects that were seen in combination treatments that accounts for less than equals to


4/5

20 percent. They are hand foot syndrome otherwise known as plamar- plantar erythrodythesia,

abdominal pain, anorexia, constipation and nail disorder.

Currently research is going on to see its therapeutic effects to treat Hodgkins lymphoma, it also

showed some positive results in treating pancreatic cancer which is in phase II trial and the

combination therapy is going on. This drug is effectively given intravenously and along with oral

dosage of Capecitabine. But before the infusion of this drug one allergy reduction medication is

given so that no allergy condition develops after receiving the treatments. While this drug is

administered for every three weeks, the infusion process is a bit time taking that is it takes

generally three hours for completion of the process.

REFRENCES

Balog, D. M.; Meng, D.; Kamanecka, T.; Bertinato, P.; Su, D.-S.; Sorensen, E. J.; Danishefsky,

S. J. (1996). "Totalsynthese von ()-Epothilon A".Angew. Chem. 108 (2324): 2976

Ganguly A, Yang H, Cabral F, (2010), Paclitaxel-dependent cell lines reveal a novel drug

activity.Mol Cancer Ther. Nov;9(11):2914-23

Goodin S, Kane MP, Rubin EH (May 2004). "Epothilones: mechanism of action and biologic

activity".J. Clin. Oncol. 22 (10): 201525.

Jordan MA, Leslie W, Microtubules as a target for anticancer drugsApr 4, 2004, "[1]

Journal of Clinical Oncology, (2007) ASCO Annual Meeting Proceedings Part I. Vol 25, No.

18S (June 20 Supplement), 2007: 1006

Lee A Y et al, (2005), Randomized comparison of low molecular weight heparin and coumarin

derivatives on the survival of patients with cancer and venous thromboembolism, Journal of

Clinical Oncology,Vol 23, p 2123-2129.

Ojima, I.; Vite, G.D.; Altmann, K.H.; (2001) Anticancer Agents: Frontiers in Cancer

Chemotherapy. American Chemical Society, Washington, DC.
http://www.jco.org/cgi/content/full/22/10/2015/http://www.jco.org/cgi/content/full/22/10/2015/http://www.ncbi.nlm.nih.gov/pubmed/15057285http://www.ncbi.nlm.nih.gov/pubmed/15057285http://www.jco.org/cgi/content/full/22/10/2015/http://www.jco.org/cgi/content/full/22/10/2015/


5/5

Rosenberg, Steven; DeVita, Vincent T.; Hellman, Samuel (2005). Cancer: Principles & Practice

of Oncology (7th ed.). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-4450-4.
http://en.wikipedia.org/wiki/International_Standard_Book_Numberhttp://en.wikipedia.org/wiki/Special:BookSources/0-7817-4450-4http://en.wikipedia.org/wiki/Special:BookSources/0-7817-4450-4http://en.wikipedia.org/wiki/International_Standard_Book_Number

Documents

EPOTHILONES