Nucleic Acid Based Cancer Therapies

State features of DNA as a drug target

Drugs target either major groove or minor groove. DNA possess a number of nucleophilic sites (reactive towards electrophiles). Intercalation (drugs can slide between base pairs). Non-covalent interactions. Drugs have different selectivities

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What are the types of DNA adducts?

DNA cleavage, intercalation, intra-strand cross-link, interstrand cross-link, topoisomerase adduct, mono-adduct

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Give examples of methylating agents

Dacarbazine, procarbazine, temozolomide

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Give examples of alkylating agents

Carbinolamines, cyclopropanes

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Give examples of cross-linking agents

Nitrogen mustards, aziridines, mitomycin C, epoxides, methanesulphonates, nitrosoureas, platinum complexes, sequence selective DNA cross-linking agents

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Give examples of intercalating agents

Antracyclines, antracenes, phenoxazines

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What are the types of topoisomerase inhibitors?

Topoisomerase I Inhibitors. Topoisomerase II Inhibitors

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Give examples of DNA cleaving agents

Bleomycins, enediynes

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Give examples of novel nucleic acid based approaches

Quadruplex binding and telomere inhibition. Transcription factor binding inhibition. DNA repair inhibition (synthetic lethality). Epigenetics. RNA targeting (e.g. RNAi and anti-sense). CRISPR- Cas9 gene editing, other approaches

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What is the basis for their selective toxicity towards tumour cells? (1)

Difference in growth rate of populations of cancer cells compared to normal cells (explains toxicity). Reduced capability of cancer cells to repair DNA lesions compared to normal cells (apoptosis)

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What is the basis for their selective toxicity towards tumour cells? (2)

Some DNA interactive agents selectively target specific DNA regions (G-C) which may be prevalent in some tumour cells (Burkitt's lymphoma). May block action of key transcription factors up-regulated in tumour cells compared to healthy cells

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Describe the importance of DNA repair pathways in mechanism of action of DNA-interactive anticancer agents

If a cell cannot repair DNA damage caused by DNA-Interactive Agents, then p53 will direct cell into “Programmed Cell Death” (also known as “Apoptosis”). DNA Repair Pathways may be damaged in cancer cells - genomes evolve/become increasingly mutated

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Which toxicities are associated with DNA-interactive anti-cancer agents?

Short term S/E of DNA interactive drugs - alopecia, GI toxicity (mucositis, diarrhoea), nausea and vomiting, reversible bone marrow suppression (most dangerous). Lung and skin toxicities (e.g. bleomycin)

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What are the two problems associated with prolonged usage? (1)

Gametogenesis is affected and sperm storage is recommended in male patients prior to treatment. Ovarian tissue can also be stored for women

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What are the two problems associated with prolonged usage? (2)

Prolonged use in combination with radiotherapy can increase incidence of acute non-lymphocytic leukaemia/sarcomas occurring later in life du to DNA damage caused by treatments

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Give examples of points of nucleophilicity in DNA

Major and minor grooves. Within nucleophilic bases. All potential reaction points are nucleophilic. Electrophilic BNF drugs interact with nucleophilic DNA. GC base pairing. AT base pairing (various drugs sensitive to particular base pairs)

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Which class of drugs was the first DNA-interactive agents?

Nitrogen mustards

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Describe features of methylating agents (1)

E.g. Dacarbazine, procarbazine and temozolomide. Work by methylating guanine bases within major groove of DNA at guanine N7 and O6 positions

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Describe features of methylating agents (2)

This is distinct from ET-743 and the PBDs which alkylate the N2 of guanine in the minor groove thus forming bulky adducts which block DNA processing.

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Describe features of dacarbazine (1)

Wide spectrum of activity ranging from malignant lymphomas to melanomas and sarcomas. Initially thought to inhibit purine biosynthesis but actually demonstrated that enzymic N-demethylation occurs in vivo

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Describe features of dacarbazine (2)

Forms 5-aminoimidazole-4-carboxamide and a transient methyldiazonium ion. Through radiolabeling experiments it has been shown that the latter methylates DNA at guanine N7 positions. Has irritant properties. S/E - myelosuppression, nausea/vomiting

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Describe features of dacarbazine (3)

Used for Hodgkin's disease

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Describe features of procarbazine (1)

First synthesized as a mono-amine oxidase inhibitor. Later discovered that it had significant activity in lymphomas/carcinoma of bronchus. Also a prodrug form of CH3+ ion

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Describe features of procarbazine (2)

MOA - metabolic N-oxidation to an azoprocarbazine species, followed by subsequent rearrangement to produce either methyl diazonium or methyl radicals which act as DNA methylating agents towards guanine residues.

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Describe features of procarbazine (3)

Used for Hodgkin's disease in combination treatment. S/E - nausea, myelosuppression, hypersensitivity rash.

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Describe features of procarbazine (4)

The mild monoamine-oxidase inhibition effect of procarbazine does not require any dietary restriction, however alcohol ingestion may cause a disulfiram-like reaction

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Describe features of temozolomide (1)

Treatment for malignant glioma and melanoma. Dose-limiting toxicity (bone marrow suppression). Good PKs. Penetrates CNS (brain tumours)

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Describe features of temozolomide (2)

MOA - chemical cleavage of tetrazinone ring to liberate 5-aminoimidazole-4-carboxamide and the highly reactive methyldiazonium methylating species

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Describe features of temozolomide (3)

After methylating DNA (or otherwise decomposing by reacting with water to give methanol) the latter forms N2, and it is the generation of the small stable molecules 5-aminoimidazole-4-carboxamide, CO2 and N2 that provides the driving force for MOA

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Describe features of temozolomide (4)

Also prodrug for CH3+ ion form. A fragment of duplex DNA is shown with a methylated guanine base

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Describe features of the biological mechanism of action (1)

Antitumour activity of temozolomide correlates with the accumulation of agent in tumours where it methylates the guanine-O6 and N7 positions in the major groove of DNA in tumour cells

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Describe features of the biological mechanism of action (2)

Selectivity at cellular level may be attributable to slightly different pH environments of normal vs malignant tissues in brain, coupled with differential capacities to repair methylated lesions by O6-alkyl-DNA alkyltranferase (ATase)

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Describe features of the biological mechanism of action (3)

At a biochemical level, it has now been established that temozolomide’s activity depends on the operation of the mismatch repair enzymes (MMRs) which detect the wobble base-pair formed during replication of drug-modified DNA

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Describe features of the biological mechanism of action (4)

Enzymes replicating DNA get confused (G-T base pairing resembles A-T) – wobble base pair (MMR enzyme remove T and try to incorporate suitable base, results in adding T back on again, endless cycle), P53 protein recognises issue, triggers apoptosis

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Describe the development of resistance (1)

To protect against such events, repair proteins have evolved, O6- and N7-alkylguanine-DNA alkyltranferases (ATases), that cleave O6- and N7-modifications stoichiometrically to restore native guanine bases

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Describe the development of resistance (2)

Base modified by temozolimide leads to mechanism of resistance - response to tumour to drug depends on MMR levels and ATase expression. Screen patients (maximum treatment benefit with ATase-ve and MMR +ve)

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Describe features of carbinolamines (1)

Ecteinascidin-743. Alkylates the N2 of guanine in the minor groove thus forming a bulky adduct that interferes with DNA processing. Used against melanoma, breast, ovarian, colon, renal, lung, prostate carcinomas

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Describe features of carbinolamines (2)

MOA involves covalent binding to the N2 position of guanine in the minor groove of DNA causing the double helix to bend towards the major groove. Subunits A/B (framework of covalent interaction with minor groove of DNA double helix)

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Describe features of carbinolamines (3)

Subunit C (protrudes DNA duplex, interacts with adjacent nuclear proteins, accounts for cytotoxicity)

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What is the biological mechanism of action for ET-743? (1)

Traps nucleases in a malfunctioning nuclease-(ET-743)-DNA adduct complex, thereby inducing irreparable single-strand breaks in the DNA

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What is the biological mechanism of action for ET-743? (2)

Induces strong perturbation of the cell cycle with delay of cell progression from G1 to G2 phase, an inhibition of DNA synthesis and cell cycle arrest in G2 phase resulting in p53- independent apoptosis.

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What is the biological mechanism of action for ET-743? (3)

Selectively inhibits transcriptional activation of the multidrug-resistance (MDR1) gene in human sarcoma cells. S/E not observed

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Describe features of cyclopropanes (1)

Cyclopropane moieties are the homocarbon analogues of aziridines and epoxides, and are also electrophilic and capable of alkylating DNA. Release of strain within 3-membered ring (driving force for alkylation). Duocarmycin interacts with cycloproprane

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Describe features of cyclopropanes (2)

CPIs and CBIs. Cyclopropane-Containing DNA A-Mono-Alkylating ADC Payloads. Cyclopropylbenzindole. Trastuzumab duocarmazine

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Describe features of cross-linking agents (1)

Contain two alkylating moieties separated by various distances by linkers.

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Describe features of cross-linking agents (2)

By alkylating two nucleophilic functional groups either on the same or opposite strands of DNA, the adducts formed represent either “intrastrand” or “interstrand” cross-links, respectively

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Describe features of nitrogen mustards

Molecules “staple” the two strands of DNA together via covalent interactions in the major groove, and presumably block replication. It can also be demonstrated that enzymes such as RNA polymerase are blocked by mustard-DNA adducts. Telomeric effect

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What are the possibilities for basis of selectivity?

Kinetic explanation (killing faster growing cells). Some cancer cells less proficient at repairing mustard adducts compared to healthy cells. GC selectivity. Some transcription factor binding sites also GC rich

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What are the possible mechanisms for development of resistance? (1)

MDR-related resistance (up-regulation of p-glycoproteins). Increase in concentration of glutathione in tumour cells (nucleophilic, forms adducts with mustards, no longer electrophilic/unable to react with DNA)

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What are the possible mechanisms for development of resistance? (2)

Some cancer cells resistant to nitrogen mustards by up-regulating repair processes, mustard adducts excised and damaged DNA re-synthesised

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Describe features of aliphatic nitrogen mustards - chlormethine (1)

The high chemical reactivity of the aliphatic nitrogen mustards towards DNA and also their vulnerability to attack by a wide range of other nucleophiles is thought to account for the observed toxicities.

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Describe features of aliphatic nitrogen mustards - chlormethine (2)

Forms a cyclic aziridinium ion. Cation formed, reacts readily with nucleophile. Attack of the N7-atoms of guanine residues in the major groove of DNA (both strands, lock strands together, SN2 process)

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Describe features of aromatic nitrogen mustards (1)

Central nitrogen atom of an aromatic mustard is not sufficiently basic to form a cyclic aziridinium ion since the nitrogen electron pair is delocalized by interaction with the π electrons of the aromatic ring

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Describe features of aromatic nitrogen mustards (2)

SN1 reaction, normal carbocation formed (Cl ion ejection, provides rate determining step). Analogues deactivated to reach DNA target sites before being degraded by nucleophiles. Oral treatment

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Describe features of chlorambucil

COOH group (improve water solubility of aromatic mustard analogue, electron withdrawing effect)

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Describe features of melphalan

Also contains COOH. Attachment of an amino acid residue (i.e., phenylalanine) might facilitate selective uptake by tumour cells in which rapid protein synthesis is occurring.

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Give examples of oxazaphosphorines

Cyclophosphamide (Endoxana). Ifosfamide (Mitoxana)

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Describe features of cyclophosphamide (1)

The design of this mustard prodrug was based on the concept that the P=O group should decrease the availability of the nitrogen lone pair in an analogous manner to the phenyl ring of the aromatic mustards, deactivating molecule to nucleophilic attack

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Describe features of cyclophosphamide (2)

P=O group might be cleaved by phosphoramidases which were thought to be over-produced in some tumour cells, thus releasing the nitrogen lone pair and restoring the electrophilicity of the molecule

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Describe features of cyclophosphamide (3)

A degree of tumour selectivity might be achieved if the phosporamidase enzymes were confined mainly to tumour cells.

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Describe features of cyclophosphamide (4)

It was later demonstrated that activation in vivo is not due to enzyme-catalysed hydrolysis of the P=O group, but rather to oxidation by liver microsomal enzymes

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Describe features of using MESNA to reduce toxicity of acrolein produced from cyclophosphamide (1)

The acrolein metabolite is excreted in the urine where it can cause hemorrhagic cystitis.

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Describe features of using MESNA to reduce toxicity of acrolein produced from cyclophosphamide (2)

Acrolein is a potent electrophile and can react with nucleophiles on the surface of cells lining the bladder. An increased fluid intake after intravenous injection can help to avoid this problem.

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Describe features of using MESNA to reduce toxicity of acrolein produced from cyclophosphamide (3)

MESNA (UromitexanTM) is routinely co-administered to “neutralize” the effect of the acrolein.

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Describe features of using MESNA to reduce toxicity of acrolein produced from cyclophosphamide (4)

Acts as a “sacrificial” nucleophile, forming a non-reactive water soluble adduct that is eliminated safely in the urine.

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Describe features of ifosfamide

Analogue of cyclophosphamide that is not technically a nitrogen mustard due to the translocation of one chloroethyl moiety to another position within the molecule. But similar spectrum activity to cyclophosphamide. MESNA co-prescribed

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Describe features of nitrogen mustards

The combination of a mustard and an oestrogen which appears to provide both an antimitotic effect and (by reducing testosterone levels) a hormonal effect

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Describe features of estramustine phosphate

Combination of an oestrogen and chlormethine (mustine) unit joined through a carbamate linkage. Alkylation/cross-link DNA

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Describe features of bendamustine

Forms both intra- and inter-strand cross-links between DNA bases

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Describe features of aziridines (1)

Ring-opening of the aziridines with nucleophiles is slower compared to the fully-charged aziridinium ions of the mustards. However, depending upon the pKa of the aziridine nitrogen, there is likely to be significant protonation at physiological pH,

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Describe features of aziridines (2)

Meaning that, in practice, the aziridinium ion may be the reactive species.

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Describe features of mitomycin C (1)

A naturally-occurring antitumour antibiotic rich in chemical functional groups. MOA involves - quinone, aziridine and carbamate moieties. Bioreductive agent. DNA cross linking properties. MOA - bioreductive trigger (chemical mechanism)

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Describe features of mitomycin C (2)

Bioreductive conditions that can exist at the centre of tumours (particularly larger ones) are thought to account, in part, for the tumour selectivity of mitomycin (mechanism)

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Describe features of mitomycin C (3)

Treats upper GI, breast cancers. Can cause delayed bone-marrow toxicity and so is usually administered at 6-weekly intervals. Prolonged use - permanent bone marrow damage, lung fibrosis, renal damage. Acute skin irritation at injection site

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Describe features of epoxides

Alkylate DNA. Treosulfan - prodrug that converts non-enzymatically to L-diepoxybutane via the monoepoxide under physiological conditions. Alkylation occurs at guanine bases

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Describe features of methanesulphonates (1)

Forms DNA cross-links, with the methanesulphonyloxy moieties acting as leaving groups after attack by nucleophilic sites on DNA (SN2 alkylation)

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Describe features of methanesulphonates (2)

Less S/E, but can cause myelosuppression, irreversible bone marrow aplasia (careful monitoring required). Hyperpigmentation of skin can occur as common S/E

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Describe features of nitrosureas (1)

Alkylate DNA and lead to both mono-adducts and interstrand cross-links at a number of different sites. E.g. carmustine and lomustine

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Describe features of nitrosureas (2)

MOA - mono-alkylation and cross-linking. Activity to brain/CSF/so-called sanctuary sites due to high lipophilicity. But can cause severe bone marrow toxicity, dose limiting

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Describe features of lomustine

It is mainly used to treat Hodgkin’s disease and certain solid tumours. Bone marrow toxicity delayed. Nausea and vomiting common. Permanent bone marrow damage with prolonged use

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Describe features of carmustine (1)

It is most commonly used to treat patients with myeloma, lymphoma and brain tumours. Cumulative renal damage and delayed pulmonary fibrosis may occur.

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Describe features of carmustine (2)

Gliadel wafer - implanted into socket left from tumour being removed, release drug, dissolve over time, remove cancer stem cells

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Describe features of platinum complexes

Cisplatin (testicular/ovarian cancers). MOA - platinum complexes interact with major groove of DNA forming mainly intrastrand links (guanine N7-guanine N7, guanine N7-adenine N7, guanine N7-X-guanine N7). Kinked cisplatin DNA adduct

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What is the biological mechanism of action for platinum complexes

Germ cell shave limited ability to repair cisplatin adducts compared to other cells. MOA could involve transcriptor factor inhibition, RNA transcription inhibition, DNA replication inhibition

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What are the disadvantages of platinum complexes?

S/E of cytotoxic agents - bone marrow suppression, nausea, vomiting, GI disturbances and hair loss. Peripheral neuropathy and ototoxicity. High cost due to Pt content

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Describe the uses and side effects of cisplatin

Used in metastatic germ cell cancers. S/E - nephrotoxicity, ototoxicity, peripheral neuropathy, hypomagnesaemia and myelosuppression. Requires IV hydration treatment for nausea/vomiting

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Describe features of carboplatin

Better tolerated than cisplatin (S/E, due to dose determined by renal function rather than BSA)

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Describe features of oxaplatin

Licensed for colorectal cancer in combination with fluorouracil and folinic acid. S/E - sensory peripheral neuropathy are dose limiting, GI disturbances, ototoxicity and myelosuppression. Need to monitor renal function

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Give examples of new cisplatin analogues in various stages of development

Picoplatin, Nedaplatin, Satraplatin

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Describe features of sequence selective cross-linking agents

Aim to develop agents that can span longer sequences of DNA. Agents with lower sequence selectivity leads to larger number of adducts formed, toxic S/E. Longer sequence selectivity, fewer adducts, less S/E

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Give an example of a DNA sequence selective minor groove binding agent

SJG-136. (Design concepts of PDB dimers, Rovalpituzumab tesirine, A-A cross linkers)

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Describe features of intercalating agents

MOA - insertion between the base pairs of DNA, perpendicular to the axis of the helix. Effect on DNA - changes structure of DNA

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What are the types of intercalating agents?

Anthracyclines, anthracene, phenoxazine, radiomimetics

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Describe features of anthracyclines

Possible MOAs - inserts between DNA base pairs to interfere with transcription, form complexes with topoisomerase enzymes and DNA to cause strand to break, binds to cell membranes to alter fluidity, free radical production

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Describe features of doxorubicin (1)

Used to treat the acute leukemias, lymphomas, and a variety of solid tumours including carcinoma of the breast, lung, thyroid and ovary, as well as soft-tissue carcinomas

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Describe features of doxorubicin (2)

Given by injection into a fast running infusion, usually at 21 day intervals, although care must be taken to avoid local extravasation which can cause severe tissue necrosis. S/E - nausea, vomiting, myelosuppression, alopecia, mucositis

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Describe features of limiting cardiotoxicity of doxorubicin (1)

Higher cumulative doses are associated with cardiomyopathy, and potentially fatal heart failure can occur.

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Describe features of limiting cardiotoxicity of doxorubicin (2)

Liposomal formulations are also available which are thought to reduce the incidence of cardiotoxicity and lower the potential for local necrosis.

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Describe features of daunorubicin

Treatment of acute lymphocytic and myelocytic leukemias.

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Describe features of aclarubicin

It is used for acute non-lymphocytic leukemia in patients who have relapsed or are resistant or refractory to first line chemotherapy

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Describe features of epirubicin

A semi-synthetic analog of doxorubicin differing only in the stereochemistry of the C4-hydroxy group of the sugar moiety.

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Describe features of idarubicin

A semi-synthetic analog of daunorubicin with general properties similar to doxorubicin. The only anthracycline that can be given orally as well as intravenously.

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Describe features of anthracenes

Have three fused rings e.g. mitoxantrone

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Describe features of mitoxantrone (1)

Rich in oxygen- and nitrogen- containing substituents and side chains, and these allow extensive stabilization of the intercalated adduct by hydrogen bonding interactions.

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Describe features of mitoxantrone (2)

Binding to GC-rich sequences and, like the anthracyclines, there is evidence that DNA is cleaved although the mechanism is not thought to be linked to the generation of reactive oxygen species.

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Describe features of mitoxantrone (3)

Used for metastatic breast cancer, non-Hodgkin’s lymphoma and adult non-lymphocytic leukaemia. Myelosuppression and dose-related cardiotoxicity (S/E)

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Describe features of pixantrone

Analogue of mitoxantrone with fewer toxic effects on cardiac tissue. Acts as an intercalating agent and Topoisomerase II inhibitor. It is formulated as pixantrone dimaleate.

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Describe features of phenoxazines

Three fused six-membered rings, central ring contains oxygen and nitrogen heteroatoms. The best known member is dactinomycin that contains two cyclic peptide side chains which stabilise the drug-DNA adduct by interacting in the minor groove of DNA.

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Describe features of dactinomycin (1)

The mechanism of action appears to be dependent on its concentration, with either blockade of DNA synthesis occurring or inhibition of DNA-directed RNA synthesis thus preventing chain elongation.

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Describe features of dactinomycin (2)

Phenoxazone ring intercalates preferentially between GC base pairs where it can interact with the N2-amino groups

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Describe features of dactinomycin (3)

The cyclic peptide moieties position themselves in the minor groove and participate in extensive hydrogen bonding and hydrophobic interactions with functional groups in the floor and walls of the groove (stabilise adduct, block RNA polymerase)

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Describe features of dactinomycin (4)

Used in combination with vincristine in the treatment of Wilm’s tumour, and combined with methotrexate for gestational choriocarcinoma. The side effects of dactinomycin are similar to those of doxorubicin (cardiac toxicity is less prominent)

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In which phase of the cell cycle is cytotoxicity greatest?

In the S phase (when topoisomerase levels are at a maximum)

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Describe features of topoisomerases

DNA topoisomerases (enzymes responsible to cleavage, annealing, supercoiling DNA)

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Describe features of topoisomerase I enzymes

Remove negative supercoils in DNA without leaving damaging nicks, break one DNA strand, attach free phosphate of broken strand to tyrosine residue on enzyme, complexes to reseal two ends of DNA

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Describe features of topoisomerase II enzymes

Cleaves both strands of double-stranded DNA followed by resealing of both strands

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Describe features of topoisomerase I inhibitors

Induces DNA breaks and cell death. Camptothecin, Hycamtin, Irinotecan. Keep chromosomes wound tight, so cell cannot make proteins, leading to cell death. S/E include diarrhoea, nausea, lowered leukocyte count, damage to bone marrow

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Give an example of the use of pharmacogenomic assay to avoid serious ADRs

Test for UGT1A1 - identify patients with increased risk of severe adverse reactions (detect variations in UGT1A1 gene)

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Describe features of topoisomerase II inhibitors

Topo IIa and IIb isoforms. Etoposide, Teniposide, Ellipticene, Amsacrine (inhibits isoforms to reseal cleaved DNA duplexes), S/E - alopecia, myelosuppression, nausea, vomiting

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Describe features of DNA cleaving agents

Bind to DNA helix, cleave double-stranded helix through radical production e.g. bleomycin, calicheamicin

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State features of bleomycins

Bleomycins – doesn’t follow Lipinski’s RO5, three distinct regions (thiazoles – intercalate, between base pairs of DNA), chelation of metal ion (cause free radical formation), stabilisation of adduct. S/E - dose limiting

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Describe features of DNA quadruplex binding agents

Potentially selective modulators of gene expression by binding in promoter regions of genes e.g Quarfloxin

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Describe features of transcription factor inhibitors

Aim to selectively inhibit gene transcription with small molecules (rather than macromolecules), stop expression of oncogenes. Dervan's hairpain polyamides

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Describe features of DNA repair inhibition

PARP inhibitors (Olaparib). Inhibit PARP1 – repair cannot take place (by P53 enzyme), single stranded break becomes a double stranded break, effective for pancreatic cancer

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Describe features of epigenetics (1)

A mechanism to regulate gene expression independent of any changes to the DNA sequence. Genomics (epigenetic influence), transcriptomics, proteomics

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Describe features of epigenetics (2)

Transcription (de-methylation and acetylation). No transcription (methylation and de-acetylation)

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Describe features of RNA targeting

RNAi (cancer therapeutic), controls expression of miRNA, use in mechanism of gene silencing , challenges (IP, stability/delivery, nanoparticle approach)

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Describe features of the antisense approach (1)

Nucleus produces mRNA, ribosome, production of protein. Antisense DNA oligonucleotide locks onto RNA to form duplex, blocks transcription. Need to know sequence of gene you want to deregulate. Difficult to give nucleic acid as oral treatment

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Describe features of the antisense approach (2)

Fomivirsen and mipomersen (and more development)

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Describe features of CRISPR-Cas9 gene editing (1)

CRISPR inhibition (broken/dead Cas9 enzyme will block binding of other proteins e.g. RNA polymerase, prevent expression of gene). CRISPR activation (activated protein attached to dead Cas9 protein to stimulate gene expression of specific gene)

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Describe features of CRISPR-Cas9 gene editing (2)

Also use of epigenetics and inducible CRISPR

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Give an example of other approaches for treatment

Replace DNA in tumour cells with DNA containing 8 base pairs

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Nucleic Acid Based Cancer Therapies

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