Anticancer Drugs: Mechanisms, Strategies, and Emerging Therapies, Study Guides, Projects, Research of Pharmacology

Download Anticancer Drugs: Mechanisms, Strategies, and Emerging Therapies and more Study Guides, Projects, Research Pharmacology in PDF only on Docsity!

Anticancer Drugs

Some basic Facts about Cancer

• Cancer cells have lost the normal regulatory mechanisms that

control cell growth and multiplication

• Cancer cell have lost their ability to differentiate (that means to

specialize)

• Benign cancer cell stay at the same place
• Malignant cancer cells invade new tissues to set up secondary

tumors, a process known as metastasis

• Chemicals causing cancer are called mutagens
• Cancer can be caused by chemicals, life style (smoking), and

viruses

• genes that are related to cause cancer are called oncogenes.

Genes that become onogenic upon mutation are called proto-

oncogenes.

Anti-Cancer Strategies

Some current and prospective modalities of cancer chemotherapy

Category Function Example s Antimetabolites Interfere with intermediary metabolism of proliferating cells Methotrexate, 5-fluorouracil Monoclonal antibodies Target cancer cells that express specific antigen Herceptin (Genentech), Zevalin (IDEC Pharmaceuticals/Schering-Plough) Mitosis inhibitors Target microtubules and associated proteins required in cell division Taxol Steroid hormones Block steroid- and hormone-dependent growth of certain tumours Tamoxifen, flutamide Alkylating/cross-linking agents Damage DNA and result in death of growing cells Endoxan, cisplatin, cyclophosphamide Signal-transduction agents Modulate communication between cells Gleevec (Novartis), Tarceva (OSI), Iressa (AstraZeneca), LY900003 (ISIS 3521) (Eli Lilly) Angiogenesisinhibitors Blockblood-vesselformationtotumour Avastin(Genentech ) Histone-deacetylase inhibitors Affect tr an scriptionofgenes SAHA(Aton Pharma) Telomerase inhibitors Affect telomere maintenance required for tumour growth BIBR1532 (Boehringer Ingelheim) Antitumour antibiotics Bind DNA to prevent DNA and/or RNA synthesis Etoposide, doxorubicin sales of kinase inhibitors Gleevec Iressa Erbitux (ab) Avastin (ab)

Phases of the Cell Cycle

• G1 phase (gap 1): Cell grows in size

and prepares to copy its DNA in

response to various growth factors

• S phase (synthesis): Replication of

DNA, copying of the chromosome

• G2 phase (gap 2): Preparation for

cell division. Check copied DNA

and repair damaged copies.

• M phase (mitosis): Formation of the

mitotic spindle, and separation into

two individual cells (cell division).

Cell Death

• Necrosis is the uncontrolled (pathological) cell death. In contrast with

apoptosis, cleanup of cell debris by phagocytes of the immune system is

generally more difficult. There are many causes of necrosis including injury,

infection, cancer, infarction, toxins and inflammation. Necrosis can arise

from lack of proper care to a wound site. Usually cell outlines do not stay

intact, and cell debris is released into the environment

• Apoptosis is the programmed cell death. It is used by organisms to control

the number of cells and tissue size. The cells during apoptosis shrink, but no

uncontrolled release of cell debris into the environment occurs. The

immune system usually “cleans up” the dying cells, and the content is

recycled.

Apoptosis is triggered by an extracellular signal to the CD95 receptor. In

response to that signal a set of cysteine proteases, called caspases are

activated, that are largely responsible for the morphological changes

observed.

Routes for Apoptosis

• Two pathways for activation: i) at the plasma membrane via external

ligands upon binding to the death receptor or ii) via the mitochondrial

pathway

• Binding of external ligands such as^ tumor necrosis factor receptor^ (TNFα)

to Fas receptors of the TNF superfamily induces receptor oligomerization

and formation of a death-inducing signaling complex. This complex

recruits, via the adaptor molecule FADD (Fas-associated death domain)

multiple Pro-caspase-8 molecules, resulting in caspase-8 activation that

finally results in caspase-3 activation

• In the mitochondrial pathway release of apoptogenic factors such as

cytochrome c, Apaf-1, caspase-9-containing apoptosome complex and

inhibitors-of-apoposis proteins trigger caspase-3 activation

• Links between the two pathways exist. For example, caspsase-8 results

in cleavage of Bid, a Bcl-2 family protein, which translocates to the

mitochondria to release cytochrome c.

Regulators of Apoptosis

• The Bcl-2 family of factors regulate caspase activation either

negatively ( e.g. Bcl-2, Bcl-XL, MCL1) or positively (e.g. Bcl-XS, Bax,

BAD, BAK, BID)

• The inhibitors of apoptosis proteins (IAP) retard apoptosis
• Upstream modulators are oncogenes such as c-myc, that

activates apoptosis in a manner important in cancer therapy

• the tumor suppressor p53 induces apoptosis under certain

circumstances

Triggers Regulators (^) Executioners DNA damage cytokine star vation hypoxia detachment temperature death receptor p death domain (^) factors Bcl-2 family Myc/oncogenes cytokine-responsive kinases Apaf- caspases

cytochrome c

• Cancer cells are often called immortal since there seems to be no limit for how often they can divide
• Life-time of normal cells is limited to 50-60 cell divisions. This is regulated by telomeres. The telomeres are at the 3’ end of the chromosomes. After each replication about 50- base pairs are lost
• At some point telomeres are too short to be effective and the DNA becomes unstable thereby limiting replication. Cancer cells possess an enzyme called telomerase which maintains the length of the telomeres and thereby allows more DNA replications.

Telomeres

A few short telomeres Critically short telomeres Apoptosis Cancer (1 in 10,000,000)

Angiogenesis

• Tumors are quickly growing tissue that need to have good blood

supply.

• Angiogenesis refers to the formation of new blood vessels
• Tumor cells release growth factors such as vascular endothelial

growth factor (VEGF) or fibroplast growth factor (FGF-2) leading to

sprouting and extension of existing capillaries

• In healthy tissue repair of injured tissues is controlled by

angiogenesis inhibitors such as angiostatin and thrombospondin

• Blood vessels arising from angiogenesis are abnormal in that they

are disorganized in structure and leaky.

• These cells display integrins on their surface to protect the newly

formed cells from apoptosis

• Before angiogenesis can start the basement membrane around

the blood vessel has to be broken down (carried out by matrix

metalloproteinases (MMPs))

Intrinsic Tumor Suppression: p

• In response to DNA damage, oncogene activation or other harmful events the tumor suppressor gene p53 is induced
• various kinases phosporylate p53 which help stabilizing it. Activated p53 results in DNA binding and transcriptional activation
• MDM2^ serves to down-regulate p53, which in turn is regulated by p14ARF
• p53 triggers cell-cycle arrest in untransformed cells via cell-cycle regulators such as CDKs
• it also triggers apoptosis in transformed cells via Bax
• in most tumor cells p53 is mutated and inactivated

Intercalating agents

Mechanism of action

• Contain planar aromatic or heteroaromatic ring systems
• Planar systems slip between the layers of nucleic acid pairs and disrupt the

shape of the helix

• Preference is often shown for the minor or major groove
• Intercalation prevents replication and transcription
• Intercalation inhibits topoisomerase II (an enzyme that relieves the strain in

the DNA helix by temporarily cleaving the DNA chain and crossing an intact

strand through the broken strand.

Drugs directly interacting with DNA

Intercalating reagents (II)

• During replication, supercoiled DNA is

unwound by the helicase. The thereby

created tension is removed by the

topoisomerase II, that cuts and rejoins

the DNA strands.

• When doxorubicin is bound to the

DNA it stabilizes the DNA-topoII complex

at the point where the enzyme is

covalently bound

Natural Products in Cancer Therapy:

Bleomycins

• intercalate via the bithiazole moiety
• the N-atoms of the primary amines, pyrimidine ring and imidazole ring chelate Fe, which is involved in the formation of superoxide radicals, which subsequently act to cut DNA between purine and pyrimidine nucleotides