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Drug Treatment of Disease > Cancer (3) Anticancer Agents 2 > Flashcards

Cancer (3) Anticancer Agents 2 Flashcards

1
Q

Drugs that exploit other aspects of tumour biology

A

Selective toxicity on the basis of rapid cell division is flawed
>leads to dose limiting side effect profile

Drugs based on some other difference in tumour biology should be
>more selective
>lesser side effects
>desired dose can be adminstered

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2
Q

Drugs that exploit other aspects of tumour biology

A

Hormones and related agents

Anti-angiogenesis agents

Inhibitors of signalling pathways

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3
Q

Hormones

A

Used when tumour growth known to depend on hormones

Oestrogens
>androgen-dependent prostatic tumours

Antioestrogens
>e.g. tamoxifen
>oestrogen-dependent breast cancer

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4
Q

Angiogenesis

A

Growth of new blood vessels from pre-existing vessels

Tightly controlled part of normal physiology
>late embryonic development
>menstrual cycle
>wound healing

Necessary for growth and spread of solid tumours
>”angiogenic switch”

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5
Q

Metastasis

A

1) Cancer cells invade surrounding tissues and vessels
2) Cancer cells are transported by circulatory system to distant sites
3) Cancer cells reinvade and grow at new loaction

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6
Q

Angiogenesis - a multistep process

A

Multistep process

Degradation of basement membrane by matrix metalloproteinases

Endothelial cell
>migration
>proliferation

Formation of new matrix

Stabilisation by pericytes

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7
Q

Endothelial cell proliferation

A

Under control of a variety of growth factors

Vascular endothelial growth factors (VEGF) are major contributors
>produced by tumour as part of angiogenic switch
>drive endothelial cell proliferation, thus permitting angiogenesis to occur

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8
Q

Angiogenesis

A

Necessary for growth and spread of solid tumours

New blood endothelial cells are required as part of process
>vascular endothelial growth factors (VEGFs) control endothelial cell proliferation

Inhibitors of VEGFs could be novel antitumour agents

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9
Q

VEGFs

A

Family of related growth factors

Ligands&raquo_space; Receptors

1) Placental growth factor&raquo_space; VEGFR-1
2) VEGF-A&raquo_space; VEGFR-2 (blood vessels)
3) VEGF-B&raquo_space; ?
4) VEGF-C&raquo_space; VEGFR-3
5) VEGF-D&raquo_space; VEGFR-3

VEGFRs are ALL receptor tyrosine kinases

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10
Q

VEGF inhibitors

A

Bind to ligand
>anti-VEGF monoclonal antibodies

Inhibit receptor
>tyrosine kinase inhibitors
>Competitive receptor antagonists

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11
Q

VEGF inhibitors

Bevacizumab

A

Monoclonal antibody to VEGF
>prevent binding of VEGF to its receptors
>stop endothelial cell proliferation

Best clinical effects seen in combination with cytotoxic drugs
>e.g. metastatic colon cancer

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12
Q

Bevacizumab -MOA

A

Mechanism of action

Induction of tumour hypoxia/starvation

Reduction in VEGF-mediated increase in vascular permeability
>reduced interstitial pressure
>improved drug delivery

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13
Q

Bevacizumab - side effects

A

Side effects

Proteinuria
Hypertension
Risk of thrombosis/bleeding
Impairment of wound healing

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14
Q

VEGF RTK inhibitors

A

Small molecules that bind to active site of tyrosine kinase domain

Sunitinib
>inhibits VEGFR-1, VEGFR-2, PDGFR

Sorafenib
>inhibits above receptors, + B-RAF

Promising in renal cell carcinoma, where inhibition of multiple tyrosine kinases may be important

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15
Q

Structure of VEGF

A

Disulphide-linked dimer

Solvent exposed loops
>form two “poles” of receptor binding
>mimetics of these should act as VEGF antagonists

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16
Q

VEGFR-2 Bioassay

A

Monomeric monocyclic peptides

Compound in preclinical development (vegenics Ltd)

17
Q

Chronic Myeloid Leukaemia (CML)

A

Accounts for 15% of adult leukaemias

Patients express a constitutively active kinase (BCR-ABL kinase)
>chromosomal translocation event gives rise to “Philadelphia chromosome”
>results in fusion of two genes BCR and ABL
(ABL normally a tightly regulated tyrosine kinase)
>BCR-ABL essential for leukaemic cell survival

Poor prognosis (median survival 6 years)

18
Q

Imatinib mesylate to treat CML

A

Small molecule tyrosine kinase inhibitor

Inhibits BCR-ABL kinase
>binds to kinase domain
>stabilises protein in closed, inactive conformation

Registered for use treatment of CML in US in May 2001

19
Q

Imatinib mesylate efficacy

A

Inhibit growth of BCR-ABL Kinase expressing cells in vitro

Suppressed growth of BCR-ABL expressing human tumours in mice

Phase I trial
>normalisation of blood counts in 95% of patients (haematologic response)
>reduction in Philadelphia chromosome-positive cells
(cytogenic response)

Phase III
>found to be better (haematologic and cytogenic) than standard cytotoxic treatment

20
Q

Clinical use of imatinib

A

Slows progression of CML

NOT a cure

Side effects not insignificant
>nausea, vomiting, muscle cramps
>liver toxicity, severe fluid retention

Resistance is common

21
Q

Drug resistance

Common problem

A

Common problem

Primary
>when drug first given

Secondary
>develops during treatment

Need to increase dose for same killing effect
>therefore increased side effects
>eventually will limit effectiveness of chemotherapy

22
Q

Drug resistance

Tumour cells primed to develop resistance

A

Tumour cells primed to develop resistance

High cell number

Rapid Growth rate

High mutation rate
>from result of loss of function to tumour suppressor genes

Drug treatment inherently selects for resistant cells

23
Q

Drug resistance mechanisms

A

Decreased intracellular accumulation

Increased expression of drug transport protein P-glycoprotein
>protection against environmental toxins
>causes active efflux of drugs
>can pump out more than one type of drug, so can be responsible for resistance to multiple drug classes

24
Q

Drug resistance mechanisms - contd

A

Reduced uptake by cell
>e.g. methotrexate and reduced expression of folate carrier

Reduced activation by cell
>e.g. 5-Fluorouracil and reduced activation by phosphorylation

Increased inactivation by cell
>inactivation of antimetabolites by deaminase

25
Q

Drug resistance mechanisms

Insensitivity to apoptosis

A

Loss of p53 tumour suppressor function
>normally, cells with damaged DNA shunted through apoptosis

Leukaemias, lymphomas, testicular cancers
>wild-type p53
>highly responsive to chemotherapy

Pancreas, lung and colon cancer
>p53 mutations
>poorly responsive to chemotherapy

26
Q

Drug resistance mechanisms

Imatinib resistance

A

Imatinib resistance

Mutations in BCR-ABL prevent adoption of closed conformation, hence no imatinib binding

New classes of TK inhibitors
>bind irrespective of open-closed formation
>greater affinity against wildtype
>bind to imatinib-resistant mutants

27
Q

Cancer chemotherapy

A

Cytotoxic drugs still provide mainstay of therapy

Newer agents
>more selective
>fewer, less dose-limiting side effects

Resistance still a problem

Drug Treatment of Disease (14 decks)

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