Cytotoxic therapy for cancer (DONE) Flashcards
Cancer general conisderations
Cancer arises from loss of normal growth control
Cancer is a disease of genetic origin, involving dynamic changes in the genome
Cells in a tumour descend from one common ancestral cell that at one point (usually decades before a tumour becomes palpable) initiated a program of inappropriate reproduction
Tumour formation in humans is a multistep process (age-dependent incidence implicating four to seven rate limiting events)
Cancer: a genetic disease
The malignant transformation comes about through the accumulation of mutations in specific classes of the genes within it
Two gene classes play particularly important roles in tumour genesis: proto-oncogenes and tumour suppressor genes
Cancer cells acquire defects in regulatory circuits that govern normal cell proliferation and homeostasis
Cancer, in many senses, is a hugely complex disease; however, the principles underlying tumour genesis can be understood by the hallmarks of cancer
The hallmarks of cancer
Self-sufficiency in growth signals
Insensitivity to growth-inhibitory signals
Evasion of programmed cell death (apoptosis)
Limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis
Plus emerging hallmarks of energy metabolism reprogramming, evading immune destruction and creation of a tumour microenvironment
Self sufficiency in growth signals
Normal cells only divide when instructed to do so by other cells in their vicinity, ensuring that each tissue maintains an appropriate size and architecture
Cancer cells, in contrast, become deaf to the usual controls on proliferation and follow their own agenda for growth
Growth signals are transmitted into the cell by trans-membrane receptors that bind distinctive classes of signalling molecules
Proto-oncogenes and signalling systems
Many proto-oncogenes encode for proteins that relay growth-stimulatory signals from outside the cell to the nucleus
Growth factors released by cells bind to specific receptors on the surface of neighbouring cells
Receptors span the outer membrane of the cell, and convey proliferative signals to a chain of proteins in the cytoplasm
The succession of relay proteins ends in activation of transcription factors which activate genes that help to usher the cell through its growth cycle
Insensitivity to growth-inhibitory signals
Cancer cells can also devise ways to evade or ignore braking signals issued by normal neighbour cells
The most important of these code for the nuclear proteins p53 and pRB
The p53 protein (the guardian of the genome) can halt cell cycle progression in response to DNA damage and induce apoptosis; mutant p53 is involved in around 50% of all cancers
The RB protein is the master brake of the cell cycle
What do proto-oncogenes do?
Proto-oncogenes encourage cell growth; however, when mutated can drive excessive multiplication
What do tumour suppressor genes do?
Tumour suppressor genes normally act as a brake on excessive growth; however, when mutated can contribute to inappropriate proliferation
Cancer therapy
In clinical practice cancers are treated by several approaches: surgery, radiotherapy, anticancer drugs
Anticancer drugs can be divided into various classes: cytotoxic or chemotherapeutic drugs, anti-hormonal treatments, agents directed to tumour biology and gene therapy
Aims of treatment
Curative- kill all the cancer cells present
Palliative- reduce tumour load and improve symptoms
Adjuvant- kill remaining cancer cells after surgery or radiotherapy
Rational for cytotoxic therapy
Cells divide by an ordered sequence of molecular events termed the cell cycle
Cytotoxic drugs target these activities
Factors affecting response to cytotoxics
Growth fraction
Type of tumour
Tumour burden, stage and spread
Health, age and pre-existing medical conditions
How are cells at different stages of the cell cycle affected by cytotoxics?
Cells in cell cycle- killed by most cytotoxic drugs
Cells in G0- can be killed once they enter cell cycle
Cells terminally differentiated- unaffected by cytotoxic drugs
Growth fraction
Cytotoxic drugs are more effective if the cancer is dividing faster as more cells are in growth phase
Burkitts’ lymphoma- doubles in 24 hours- 96-98% of cells in cell cycle
Breast cancer- double in 3 months- 5-60% of cells in cell cycle
Prostate cancer- double in 8 months- 0.5-15% of cells in cell cycle
Tumour size
Geometric resistance increases with size limiting drug and oxygen delivery to large tumours
Blood flow across a capillary bed controls drug delivery
Tumour stage, grade and spread
Stage local or invasive
Metastatic spread
Histological grade: increasing anaplasia, increasing mitotic activity, increasing genetic instability
Health, age and pre-existing medical condition
Cytotoxic therapy is debilitating and not suitable for old/frail individuals
Liver disease- drug metabolism, serum binging proteins affected
Anaemia and immune disorders- cytotoxics exacerbate
Kidney disease- drug excretion, toxicity problems
Lung/heart disease- precludes use of certain cytotoxics
Factors affecting drug delivery to drug tumours
Blood flow across a capillary bed
Geometric resistance within the tumour
Oral administration altered by drug absorption and first pass metabolism in the liver
Drug delivery can also be influenced by plasma protein binding
Therapeutic index- schedule and route of administration
Intermittent intensive course are better than continuous (daily therapy)
Intravenous infusion of cytotoxics often best
Regional administration achieve higher drug concentrations in the vicinity of the tumour e.g. intraperitoneal for ovarian cancer, intrapleural for mesothelioma
Therapeutic index altered by drug metabolism
Many cytotoxic drugs require chemical or enzymatic activation in either normal or tumour tissue
Therapeutic index altered by drug resistance
Decreased drug uptake/increased drug removal
Decreased drug activating enzymes enzymes/increased drub inactivating enzymes
Increased levels of target enzyme
Altered affinity of target
Increased DNA repair
An alternative metabolic pathway
What are the targets for cytotoxic drugs?
Specific enzymes involved in the synthesis of nucleotides
Nucleic acids- DNA and RNA
Microtubule dynamic involved in mitosis
Classes of cytotoxic drugs
Antimetabolites- target enzymes involved in nucleotide synthesis
Drugs targeting DNA structure and template activity
Mitotic arrest agents target microtubules
Sites of action of cytotoxic drugs
Antimetabolites- nucleotide synthesis
Alkylating agents- DNA
Intercalating agents- DNA transcription and duplication
Topoisomerase inhibitors- DNA transcription and duplication
Mitotic inhibitors- mitosis
Combination chemotherapy
Single drug treatments are very rare
Combination therapy is used for virtually all neoplasms
Convincing rational for combination therapy is its clinical success
Bone marrow toxicity is the main dose limiting factor
Aim of combination therapy
Different targets and mechanisms of action and resistance- activity
Compatible side effects on different organ targets- safety
Combination chemotherapy guidelines
Active against the tumour type
Act on different biochemical targets
Act on different phases of the cell cycle
Affect different organs and tissues
Have minimum or no overlapping toxicity
Are optimum for each drug with consistent timing of the doses
Therapy cycles dictated by bone marrow recovery
Clinical response measure of successful combination
Antimetabolites
Analogues of substrates and cofactors of the enzymes involved in nucleotide synthesis
Mercaptopurine and Thioguanine- purine analogues inhibit several enzymes in purine synthesis
5-Fluorouracil- a pyrimidine analogue inhibits thymidylate synthase
Methotrexate- a cofactor analogue inhibits an enzyme generating folate essential for purine synthesis
Drugs work in S phase of the cell cycle
Mechanism of action of 5FU
Covalently inactivates thymidylate synthase
A stable ternary covalent complex is formed between 5-FdUMP, reduced folate derivative and thymidylate synthase
Alkylating agents
Nitrogen mustards, nitrosureas and the platinum antitumour compounds
Form strong chemical bonds with electron rich atoms such as nitrogen in DNA mainly the N7 position of deoxyguanylates
Using drugs with two alkylating groups results in covalent cross linking of adjacent strands of DNA
Most alkylating agents require chemical or enzymatic activation
Primary cytotoxic action is inhibition of DNA synthesis because of the crosslinking in the strands
All phases of the cell cycle are susceptible
Cyclophosphamide mechanism of action
More selective mustard: P=O group should decrease availability of nitrogen lone pair
Acrolein removed by co-administration of 2-mercaptoethanesulphonate as a sacrificial nucleophile
Wide spectrum of activity ranging from malignant lymphomas and lymphoblastic leukaemia to carcinomas of the bronchus, breast, ovary and various sarcomas
Mechanism of action: platinum compounds
Series of reactions to form active compound in which chloride ions are replaced by a hydroxyl group
Effects of alkylating agents on DNA
Crosslinked guanine bases- DNA replication impaired
Guanine N7 alkylation can give an enol tautomer which can bind to thymidine- mismatching of bases leading to defective coding of proteins
Guanine N7 alkylation can cause cleavage of imidazole ring- excision of guanine residue leading to DNA breakage
DNA intercalators: anthracyclines and antibiotics
Mainly antibiotics of microbial origin and include- doxorubicin, daunorubicin, belomycin, actinomycin D, mitomycin C
The planar aromatic ring structure can insert into the space between successive nucleotide base pairs distorting the a helix of DNA impairing binding of essential enzymes
Binding is reversible and stabilised by the hydrophobic interaction between the opposing aromatic rings of the drug and adjacent DNA bases, also by ionic binding between drug and charged centre of DNA
Intercalators act in late G1, S and early G2 phases of cell cycle
Mechanism of action of the topoismoerases
Topoisomerase enzyme binds, cuts strand, strand rotates and re-anneals strand of supercoiled DNA
The enzymes action results in removal of torsional stress such as unknotting and relaxation
Topoisomerase I inhibitors: Camptothecines
A Camptothecin derivative CPT 11, Irinotecan is converted in vivo to active 7-ethyl derivative
Stabilization of cleavable complex- inhibition of ligation step
Replication fork arrest and irreversible DNA breakage
Topoismoerase II inhibitors: epipodophyllotoxins
Glycosides derivatives etoposide and teniposide are cytotoxic and are used in chemotherapy regimes
Topoisomerase II principle function is to catalyse the separation of daughter DNA strands just prior to mitosis
The drug (etoposide) stabilises enzyme DNA complex, inhibiting the annealing process leaving DNA double strand breaks not amenable to repair
They cause arrest of cell cycle in G2 phase
Mitotic inhibitors
Mitotic inhibitors arrest the cells in mitosis and target the microtubules
Microtubule dynamics indicate that microtubules are inherently polar structures that rapidly assemble and disassemble. In cells, one end of a microtubule is usually anchored to an organising centre (aster), the other end is either growing or shrinking
Mitotic inhibitors B Taxanes
Taxanes (Taxol) bind with high affinity to polymerised microtubules of the mitotic spindle
The interaction is reversible
They bind to B-tubulin at specific amino acid residues
They block in M phase of cell cycle, inhibiting spindle dissolution
Mechanism of action of mitotic inhibitors
Vinca alkaloids prevent assembly of microtubule to form spindle in prophase
Taxanes inhibit disassembly of the spindle in telophase
Example of antimetabolites- purine analogues
6-thoioguanine
6-mercaptopurine
Example of antimetabolites- pyrimidine analogues
5-FU
Cytosine araboniside
Example of antimetabolites- folate antagonists
Methotrexate
Example of alkylating drugs- nitrogen mustard compounds
Melphalan
Clorambucil
Cyclophosphamide
Example of DNA intercalators- anthracyclines, antibiotics
Doxorubicin Daunorubicin Bleomycin Actinomycin D Mitomycin C
Example of topoisomerase I inhibitors- camptothecines
Irinotecan
Example of topoisomerase II inhibitors- epipodophyllotoxins
Etoposide
Teniposide
Example of mitotic inhibitors
Vinca alkaloids
Taxanes
