Chapter 7. 4. Plant products

抗肿瘤植物药　

Chapter 7. 4. Plant products

Paclitaxel (Taxol) 紫杉醇

Undisturbed Pacific Yew bark contains paclitaxel

The bark is peeled and processed to provide paclitaxel

Discovery of Paclitaxel

On August 21st, 1962, botanists, Arthur S. Barclay, collected bark from a single Pacific yew tree, Taxus brevifolia, in a forest north of the town of Packwood in Washington State as part of a four month trip collecting material from over 200 different species. One of the Taxus samples was found to be cytotoxic in a cellular assay on 22 May 1964.

Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall in Research Triangle Park, North Carolina, began work on fresh Taxus samples, isolating the active ingredient in September 1966. They named the pure compound 'taxol' in June 1967.

Discovery of Paclitaxel

By 1969 28kg of crude extract had been isolated from 2,600 pounds of bark, yielded only 10g of pure material.

BMS filed an NDA which was given FDA approval at the very end of 1992.

Taxol content varies in the Yew tree (0.001 to 0.01 % of the dry bark weight). It is generally considered to take 3 to 10 trees per patient.

Based on data from the U.S. Forest Service from 1992, 36000 trees are required to provide 327200 kg of bark (about 9 kg/tree) from which 24 kg of taxol can be extracted. (about 0.66 g/tree).

Approximately 1 kg is required for 480 cancer patients or 2.08 g per person or 3.15 trees per person. Others have claimed this number can be as high as 10 trees per person depending on the size of the trees

Currently, all paclitaxel production for BMS uses plant cell fermentation (PCF) technology developed by the biotechnology company Phyton and carried out at their plant in Germany. This starts from a specific taxus cell line propagated in aqueous medium in large fermentation tanks. Paclitaxel is then extracted directly, purified by chromatography and isolated by crystallization. Compared to the semisynthesis, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.

β-(Benzoylamino)-α-hydroxy-,6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca(3,4)benz(1,2-b)oxet-9-ylester,(2aR-(2a-α,4-β,4a-β,6-β,9-α(α-R*,β-S*),11-α,12-α,12a-α,2b-α))-benzenepropanoic acid

HO O OAc

HO

R

H

PhO

R

R

ROH

O

AcO O

Ph

O

OH

NHPh

O

R= CH3

Paclitaxel

Mechanism of action: Taxol binds to polymerised tublin promoting microtubule formation and microtubule stabilisation against disassembly and hence inhibiting mitosis and therefore cancer growth

Clinical use: Ovarian cancer, breast cancer, and lung cancer

Restenosis: Paclitaxel is used for the prevention of restenosis (recurrent narrowing) of coronary stents; locally delivered to the wall of the coronary artery, a paclitaxel coating limits the growth of neointima (scar tissue) within stents. Paclitaxel drug eluting coated stents are sold under the trade name Taxus by Boston Scientific in the United States.

Similar drugs

The closely related taxane docetaxel has a similar set of clinical uses to paclitaxel.

In January 2005, the FDA approved ABRAXANE (protein-bound paclitaxel) for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. In this preparation, paclitaxel is bonded to albumin as the delivery agent as an alternative to the often toxic, solvent delivery method.

Protein kinase modifies other proteins by adding phosphate groups to them (phosphorylation). Up to 30% of all proteins may be modified by kinase activity. The human genome contains about 500 protein kinase genes; they constitute about 2% of all eukaryotic genes.

A kinase remove a phosphate group from ATP and covalently attaches it to one of three amino acids that have a free hydroxyl group. Most kinases act on both serine and threonine, others act on tyrosine, and a number (dual specificity kinases) act on all three.

Chapter 7. 5. Kinase inhibitors

Tyrosine ATP

OH

H2NH

O

OH

N

N N

N

H2N

O

OHHO

OP

O

O

OP

O

O

OP

O

O

O

O

H2NH

O

OH

P

O

O

O

+

Tyrosine kinase

Currently approved anticancer protein kinase inhibitor drugs

Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Nilotinib, Sorafenib, Sunitinib, Vandetanib (ZD6474)

                           

Imatinib

                           

Imatinib

                           

Imatinib

                           

Imatinib

Imatinib is currently marketed as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs). It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells.

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously active tyrosine kinase, imatinib is used to decrease bcr-abl activity.

Erlotinib hydrochloride (trade name Tarceva, Genentech/OSIP, originally coded as OSI-774) is used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. Rrlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer.

Gefitinib is used in the treatment of certain types of cancer. Acting in a similar manner to erlotinib (Tarceva). Gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa.

Sunitinib (marketed as Sutent, and previously known as SU11248) is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications. Sunitinib has since become the standard of care for both of these cancers, and is currently being studied for the treatment of many others

Chapter 7. 6. Anticancer Monoclonal Antibodies ( 单克隆抗体）　

Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2/neu (erbB2) receptor. Trastuzumab's principal use is therapy in breast cancer in patients whose tumors over express this receptor. Trastuzumab is administered either once a week or once every three weeks intravenously for 30 to 90 minutes.

HER2 is expressed in 25-30% of early-stage breast cancer patients. Some recent clinical trials have found trastuzumab reduces the risk of relapse in breast cancer patients by 50% when given in the adjuvant setting for one year.

Herceptin

Chemical Formula:C: 6470, H: 10012, N: 1726, O: 2013, S: 42

Mol. Mass: 145,531.5 g/mol

Rituximab sold under the trade names Rituxan® and MabThera®, is a chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders.

Bevacizumab (trade name Avastin) is against vascular endothelial growth factor. It inhibits tumor growth by blocking the formation of new blood vessels. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States. Bevacizumab was approved in 2004 for use in combination with standard chemotherapy in the treatment of metastatic colon cancer and most forms of metastatic non-small cell lung cancer.

Gemtuzumab ozogamicin (marketed as Mylotarg) is used to treat acute myelogenous leukemia. It is a monoclonal antibody to CD33 linked to a cytotoxic agent, calicheamicin. CD33 is expressed in most leukemic blast cells.

Rituximab sold under the trade names Rituxan® and MabThera®, is a chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders.

KILLER Rituxan kills B cells associated with non-Hodgkin's lymphoma by binding to the cells' CD20 receptor and thus inducing one or more of three mechanisms--complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and/or apoptosis.

COURTESY OF ANTONIO GRILLO-LÓPEZ

KILLER Rituxan kills B cells associated with non-Hodgkin's lymphoma by binding to the cells' CD20 receptor and thus inducing one or more of three mechanisms--complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and/or apoptosis.