Van tinh nguyen chapter 39-anticancer drugs
-
Upload
dimpled-dongtien -
Category
Health & Medicine
-
view
447 -
download
1
Transcript of Van tinh nguyen chapter 39-anticancer drugs
Van-Tinh Nguyen20141113
Course title: Special Study on Marine
Bioactive Substances
11/25/2014 1
Chemotherapeutic Drugs
• Principles of Antimicrobial Therapy
• Cell Wall Inhibitors
• Protein Synthesis Inhibitor
• Quinolones, Folic Acid Antagonists, and
Urinary Tract Antiseptics
• Antimycobacterials
11/25/2014 2
• Antifungal Drugs
• Antiprotozoal Drugs
• Anthelmintic Drugs
• Antiviral Drugs
• Anticancer Drugs
• Immunosuppressants
OVERVIEW
• Cancer is a collective term used for a group of diseases that are characterized by the loss of control
of the growth, division, and spread of a group of cells, leading to a primary tumor that invades and
destroys adjacent tissues.
• It may also spread to other regions of the body through a process known as metastasis, which is the
cause of 90% of cancer deaths. Cancer remains one of the most difficult diseases to treat and is
responsible for about 13% of all deaths worldwide, and this incidence is increasing due to the
ageing of population in most countries, but specially in the developed ones.
• With 1.3 million new cancer patients were diagnosed each year.
• Cancer is normally caused by abnormalities of the genetic material of the affected cells.
11/25/2014 3
1. Historically derived small molecules. Target DNA
structure or segregation of DNA- Conventional
chemotherapy
2. Targeted agents: Act against pathways that lead to:
• Uncontrolled proliferation
• Loss of cell cycle inhibitors
• Loss of cell death regulation
• Capacity to replicate chromosomes indefinitely
• Invade, metastasize & evade the immune system
Anti Cancer drugs
11/25/2014 4
3. Hormonal therapies
4. Biological therapies
- Therapeutic delay
- Tumor response
- Anti cancer drug toxicities
Response:- induce cancer cell death
- Tumor shrinkage with increase patient
survival
- Increase time until disease progresses
- Necrosis, apoptosis
Drug Development plan
Ivanov A.S. Protein-protein Interactions As New Targets For Drug Design: Interactive Links Between
Virtual And Experimental Approaches. Bgrs’2006511/25/2014
For a list of the anticancer agents
discussed in this presentation.
11/25/2014 6
In silico studiesIn silico is performed on computer or via computer simulation. In his talk, Miramontes used the term ”in silico” to characterize biological experiments carried out entirely in a computer.Although in silico studies represent a relatively new avenue of inquiry, it has begun to be used widely in studies which predict how drugs interact with the body and with pathogens. For example, a 2009 study used software emulations to predict how certain drugs already on the market could treat multiple-drug-resistant and extensively drug-resistant strains of tuberculosis.3There is a variety of in silico techniques, but the two that are discussed the most in connection with the Marshall Protocol are:Bacterial sequencing techniques – As an alternative to in vitro methods for identifying bacteria, various in silico methods which sequence bacterial DNA and RNA have been developed. The most commonly used use is polymerase chain reaction (PCR). PCR takes a single or few copies of a piece of DNA and increases it across several orders of magnitude, generating millions or more copies of a particular DNA sequence. PCR has allowed researchers to detect bacteria associated with a variety of conditions with increasingly high sensitivity.Molecular modeling – Part of the Marshall Pathogenesis is based on in silico work, demonstrating how drugs and other substances interact with the nuclear receptors of cells. In particular, Trevor Marshall, PhD, has used computer-based emulations to show that 25-D, one of the vitamin D metabolites, and Capnine, a substance produced by bacteria, turn off the Vitamin D Receptor. These conclusions have since been validated by clinical observations.Whole cell simulations – As described here, researchers have built a computer model of the crowded interior of a bacterial cell that—in a test of its response to sugar in its environment—accurately simulates the behavior of living cells.4
11/25/2014 7
In vivo studiesIn vivo (Latin for “within the living”) refers to experimentation using a whole, living organism as opposed to a partial or dead organism. Animal studies and clinical trials are two forms of in vivo research. In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject.
While there are many reasons to believe in vivo studies have the potential to offer conclusive insights about the nature of medicine and disease, there is a number of ways that these conclusions can be misleading. For example, a therapy can offer a short-term benefit, but a long-term harm.
11/25/2014 8
In vitro (Latin for within the glass) refers to the technique of performing a given procedure in a controlled environment outside of a living organism. Many experiments in cellular biology are conducted outside of organisms or cells. One of the abiding weaknesses of in vitro experiments is that they fail to replicate the precise cellular conditions of an organism, particularly a microbe. To cite one example among many, the lysates or extracts from culture-grown spirochetes do not reflect antigens expressed in the mammalian Borrelia:
Addressing this question is complicated by the fact that protein expression of culture-grown spirochetes does not fully resemble Borrelia in the host, i.e. the usefulness of protein lysates from culture-grown bacteria is limited as a source of antigen for ELISPOT analysis.
Stefan S. Tunev 1
Because of this, in vitro studies may lead to results that do not correspond to the circumstances occuring around a living organism.
Until the last several years, efforts to detect and identify microorganisms in the human body have depended almost exclusively on in vitro studies. As a result, many researchers began to assume that chronic diseases were not caused by microbes. The net effect of all this was that the understanding of pathogens in disease was driven by the study of well-known, easy-to-culture microbes–which, as it turns out, represent the vast minority of bacteria in the human body. By one estimate, 99.6% of the species in the human microbiota have not or cannot be characterized through in vitro techniques.2
Another example of a shortcoming of in vitro studies relates to concentrations of molecules, especially as they compete for nuclear receptors. For example, the vitamin D metabolite, 1,25-D, exerts its effects at 30 picograms per milliliter, or 0.000000000003 grams per milliliter.
Summary of chemotherapeutic agents
11/25/2014 9
Chemical structures of antimetabolites
11/25/2014 10
Talanta, Volume 85, Issue 5, 2011, 2265 - 2289
Chemical structures of microtubule
inhibitors
11/25/2014 11
Interaction of drug with target cascade
Cell death – “Execution phase”
Proteases, nucleases and endogenous regulators of cell death
pathway are activated.
11/25/2014 12
How anti-cancer drugs work
How targeted agents differ?
Cell cycle specificity of anticancer agents
11/25/2014 13
11/25/2014 14
Summary of the various mechanisms of action of anticancer agents
Summary of the various mechanisms of action of anticancer agents
11/25/2014 15
ANTIMETABOLITESCapecitabine
• Antimetabolites are structurally related to normal compounds that exist within the cell.
• They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting
their synthesis or by competing with them in DNA or RNA synthesis.
• Their maximal cytotoxic effects are in S-phase (and are, therefore, cell-cycle specific).
• Capecitabine is approved to be used alone or with other drugs to treat:
• Breast cancer that has metastasized (spread to other parts of the body) in patients whose disease has not
gotten better with other chemotherapy.
• Colorectal cancer. It is used to treat stage III colorectal cancer in patients who have had surgery to remove
the cancer. It is also used as first-line treatment of patients with metastatic colorectal cancer.
11/25/2014 16
Capecitabine mechanism of action
Three-step metabolic conversion of capecitabine to fluorouracil (FU). Capecitabine is absorbed through
the intestine and converted to 5'-deoxy-S-fluorocytidine (5'-DFCR) by carboxylesterase and then to
5'-deoxy-S-fluorouridine (5'-DFUR) by cytosine deaminize, both steps taking place in the liver. Finally,
thymidine phosphorylate converts 5'-DFUR to the active drug, FU. This occurs in both tumor and normal
tissues; however, the enzyme is found at higher concentrations in most tumor tissue compared with normal
healthy tissue.Clinical Therapeutics/Volume 27, Number 1, 2005
11/25/2014 17
11/25/2014 18
Capecitabine mechanism of actionMechanism of Action
Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both
normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine
monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).
These metabolites cause cell injury by two different mechanisms.
First, FdUMP and the folate cofactor, N5,N10 methylene-
tetrahydrofolate, bind to thymidylate synthase (TS) to form a
covalently bound ternary complex.
This binding inhibits the formation of thymidylate from 2'-
deoxyuridylate. Thymidylate is the necessary precursor of thymidine
triphosphate, which is essential for the synthesis of DNA, so that a
deficiency of this compound can inhibit cell division.
Second, nuclear transcriptional enzymes can mistakenly
incorporate FUTP in place of uridine triphosphate (UTP) during the
synthesis of RNA. This metabolic error can interfere with RNA
processing and protein synthesis.
Gemcitabine Hydrochloride - Gemzar
• Gemcitabine hydrochloride is approved to be used alone or with other drugs to treat:
• Breast cancer that has metastasized (spread to other parts of the body) and has not gotten better with
other chemotherapy. It is used with paclitaxel.
• Non-small cell lung cancer that is advanced or has metastasized. It is used in patients whose disease
cannot be removed by surgery. It is used with cisplatin.
• Ovarian cancer that is advanced and has not gotten better with other chemotherapy. It is used
with carboplatin.
• Pancreatic cancer that is advanced or has metastasized. It is used in patients whose disease cannot be
removed by surgery and who have already been treated with other chemotherapy. It is used
with paclitaxel albumin-stabilized nanoparticle formulation.
• Gemcitabine hydrochloride is also being studied in the treatment of other types of cancer.
11/25/2014 19
11/25/2014 20
Gemcitabine Hydrochloride - Gemzar
difluorodeoxycytidine 5'-triphosphate (dFdCTP).
The dFdCTP metabolite is able to inhibit the actions of several DNA
polymerases interfering thus to DNA chain elongation, synthesis or
DNA repair.
Saif MW. 2006. JOP. J Pancreas (Online) 2006; 7:337-348
Methotrexate
• Methotrexate is approved to be used alone or with other drugs to treat:
• Acute lymphoblastic leukemia that has spread to the central nervous system, or to prevent it from spreading
there.
• Breast cancer.
• Gestational trophoblastic disease.
• Head and neck cancer (certain types).
• Lung cancer.
• Mycosis fungoides (a type of cutaneous T-cell lymphoma) that is advanced.
• Non-Hodgkin lymphoma that is advanced.
• Osteosarcoma that has not spread to other parts of the body. It is used following surgery to remove
the primary tumor.
• Methotrexate is also being studied in the treatment of other types of cancer.
11/25/2014 21
Journal of the National Cancer Institute, Vol. 96, No. 2, January 21, 2004
11/25/2014 22
Methotrexate
Mechanism of Destabilization of microtubules by Vinca alkaloids
11/25/2014 23
The mitotic spindle consists of chromatin plus a
system of microtubules composed of the protein
tubulin.
The mitotic spindle is essential for the equal
partitioning of DNA into the two daughter cells
that are formed when a eukaryotic cell divides.
Several plant-derived substances used as
anticancer drugs disrupt this process by affecting
the equilibrium between the polymerized and
depolymerized forms of the microtubules, thereby
causing cytotoxicity.
Mechanism of action of the microtubule inhibitors
•Mechanism of action: microtubule depolymerization
• Vincristine binds to tubulin dimers, inhibiting
assembly of microtubule structures and arresting
mitosis in metaphase. Because vincristine's
mechanism of action targets all rapidly dividing
cell types, it not only inhibits cancerous cells but
can also affect the intestinal epithelium and bone
marrow.
• Mitotic arrest at metaphase; interferes with
chromosome segregation
•Clinical Use:
• In combination with prednisone: induction of
remission in children with acute leukemia
• Useful in treating some other rapidly
proliferating neoplasms
• Adverse Effects:
• Significant frequency of neurotoxic reactions
• Occasional: bone marrow depression
Vincristine is a Plant Alkaloids
11/25/2014 24
Vincristine
Tubulin inhibitors
STEROID HORMONES AND THEIR ANTAGONISTS
Tamoxifen
• Breast cancer treatment
• Oral administration.
• Activity against progesterone-resistant endometrial neoplasm
• Chemopreventive: women - high-risk for breast cancer
• Mechanism of Action:
• Competitive partial agonist-inhibitor of estrogen
• Binds to estrogen-sensitive tissues
• Best antiestrogen effect requires minimal endogenous estrogen presence
• Suppresses serum levels of insulin-like growth factor-1; and up-regulates local
TGF-beta production. These properties may explain tamoxifen antitumor activity in
melanoma and ovarian cancer.
• Adverse Effects:
• Generally mild
• Most frequent: hot flashes
• Occasionally: fluid retention, nausea
• Clinical Use:
• Advanced breast cancer
• Most likely to be effective if:
• Lack endogenous estrogens
• Presence of cytoplasmic estrogen receptor
• Prolongs survival {surgical adjuvant therapy} in postmenopausal
women with estrogen receptor-positive breast cancer.11/25/2014 25
Topotecan
Topotecan is used in metastatic ovarian cancer when
primary therapy has failed and also in the treatment of
small cell lung cancer.
These drugs are S-phase specific. They inhibit
topoisomerase I, which is essential for the replication
of DNA in human cells
It binds to the Topo I-DNA adduct to form a ternary
complex that prevents re-ligation of the DNA strand,
thus leading to double-strand DNA breaks and cell
death.
• Mechanism of action: interfere with activity of topoisomerase
I (cuts and religates single stranded DNA. DNA is damaged
• Clinical Uses:
• Topotecan: metastatic ovarian cancer - including
cisplatin-resistant forms (as effective as paclitaxel)
• Adverse Effects:
• Primary
• Neutropenia
• Thrombocytopenia
• Anemia
• Other
• Nausea
• Alopecia11/25/2014 26
Other
Topotecan
Key interactions in the topotecan-DNA-topo I compels
11/25/2014 27
Etoposide and teniposide activity is cell cycle dependent
and phase specific, with maximum effect on the S and G2
phases of cell division. They cause DNA damage through
inhibition of topoisomerase II, and their mechanism of
action has been studied specially for the case of etoposide.
inhibitor of the topoisomerase II–DNA cleavable complex
They block cells in the late S to G2 phase of the cell cycle
Etoposide and teniposide
•Etoposide and teniposide: structurally similar
•Mechanism of action:
• Block cell cycle: in late S-G2 phase
• Inhibition of topoisomerase II - DNA damage
•Clinical Use:
• Testicular cancer
• Small cell lung carcinoma
• Teniposide (Vumon): lymphomas
• Adverse Effects:
• Nausea
• Vomiting
• Alopecia
• Significant hematopoietic toxicity and lymphoid
toxicity
11/25/2014 28
Etoposide
Inhibitors of the binding of topoisomerase II to DNA
Etoposide is used mainly to treat testicular cancer which does not respond to other treatment and as a
first-line treatment for small cell lung cancers. It is also used to treat chorionic carcinomas, Kaposi’s
sarcoma, lymphomas, and malignant melanomas.
11/25/2014 29
Adjunct Therapies
• Adjunct therapies are given in combination with cancer chemotherapeutic
agents either to counteract side effects, such as:
• Nausea and vomiting
• To enhance their therapeutic effect.
• Types of adjunct therapies considered include:
• Anti-emetics
• Steroidal agents
• Adjuvant enzymes.
11/25/2014 30
11/25/2014 31