HIS18 HIS19 Cytotoxic Drugs In The Treatment Of Cancer I + II Flashcards
Features of cancer cell
- Uncontrolled cell proliferation (failed to respond to growth inhibition)
- Decreased cellular differentiation + Loss-of-function
- Evading immune destruction
- Ability to invade surrounding tissue
- Growth at ectopic site (i.e. Metastasis)
Tumour growth
Cancer arises from a change in one single cell (i.e. Clonal)
—> acquired different mutations
—> advantage of resistance to cell death
—> ends in marked heterogeneity of many tumour cells (characteristics different from original tissue)
Growth rate of solid tumours:
- Rapid initially —> Decrease as tumour size ↑ (∵ lack of vascularisation —> insufficient nutrients, O2)
1. Neoangiogenesis, risk of metastasis: Cell no.: 10^6 + Weight 1mg
2. Clinical diagnosis: Cell no.: 10^9 + Weight 1g
3. Symptomatic: Cell no.: 10^10
4. Lethal size: Cell no.: 10^12 + Weight 1kg —> widespread cancer developed
Clinical remission, symptomatic improvement:
- require killing >99.9% of tumour cells
—> however, remaining cells can be resistant to / not accessible by therapeutic agents
Cancer treatment
Treatment are used in combination (simultaneously / subsequently)
- Surgery (early stage solid tumours)
- Radiotherapy (high energy beam, in conjunction with surgery + drug treatment)
- ***Chemotherapy (damage dividing cancer cells, prevent reproduction)
- ***Hormonal therapy (prevent cancer growth)
- ***Targeted therapy (target specific protein / process limited to cancer cells)
- Immunotherapy
Goal of cancer treatment
- Cure
- long term, disease-free survival
- eradication of every neoplastic cells - Control of disease (treated as chronic disease)
- stop cancer from enlarging / spreading
- extend survival
- maintain best quality of life - Palliation (when control become impossible)
- alleviation of symptoms
- avoidance of life-threatening toxicity
- improve quality of life
- initial remission are transient, with symptoms recurring between treatments
- survival is extended but patient eventually die
Chemotherapy
Use of ***cytotoxic agents to inhibit growth, development, proliferation of malignant cells
Discovery:
- Sulfur mustard (alkylating agent) —> lymphoid / bone marrow hypoplasia
- dramatic reduction in tumour mass in non-Hodgkin’s lymphoma
Pharmacokinetics:
- 1st-order kinetics
—> no. of killed tumour cells proportional to dosage
—> a given dose destroy constant fraction of total tumour cells (∴ can never reach 0% (i.e. fully eradicate)) —> “Log kill”
—> chemotherapy must be repeated (single dose cannot kill all) to achieve near total kill (hope host immune response kill remaining cell)
Curative chemotherapy (>2 log kill: >99%)
- Solid tumour
- tumour burden initially reduced by surgery and/or radiation
- treatment of occult micrometastases continued after clinical signs of cancer have disappeared (i.e. Adjuvant therapy) - Disseminated cancer (e.g. leukaemia)
- combination-drug therapy reduce chance of drug resistance
- each drug have different site of action / cell-cycle specificity
- each drug have different organ toxicity
Critical points of treatment
- Early start to treatment
- Treatment must continue past the time when cancer cells cannot be detected
- Appropriate scheduling of treatment —> ensure sufficient log kill
***Chemotherapy treatment strategies
- Neoadjuvant therapy
- reduce tumour burden ***before surgery / radiation - Adjuvant therapy
- short course
- **high-dose
- **after surgery / radiation
- destroy residual tumour cells / micrometastases
- prevent recurrence - Induction therapy
- **high-dose (usually combination)
- induce complete response when **initiating curative regimen - Consolidation therapy
- given ***after induction therapy to achieve complete remission - Maintenance therapy
- ***low-dose (single / combination)
- long term basis during complete remission
- delay-regrowth of residual cancer cells - Salvage therapy
- use of potentially curative ***high-dose regimen
- symptoms have recurred / treatment by other regimens has failed
***Common SE of chemotherapy
Chemotherapy: steep dose response curve —> narrow therapeutic window —> sensitive dosing adjustment required
Most SE are dose-dependent:
1. N+V (>90% well controlled)
2. Alopecia (6 weeks after therapy, return 6-9 weeks of cessation)
3. Fatigue
4. Mucositis (usually dose too high, require minimal dose reduction)
5. Myelosuppression (monitored regularly, infection-susceptible)
6. Neurotoxicity (common with alkaloid, taxin, platin —> modified / stopped if motor function affected)
Specific SE (irreversible):
1. **Cardiotoxicity (Doxorubicin)
2. **Pulmonary fibrosis (Bleomycin)
***Some of SE can alleviated by
1. Cytoprotective drugs
2. Removing marrow prior to therapy —> re-implant it
3. Folinic acid —> Megaloblastic anaemia (Methotrexate)
4. Human granulocyte colony stimulating factor (G-CSF) —> prevent Neutropenia
Rapidly-dividing cells in healthy tissue (most commonly affected)
- fibroblasts
- GI lining
- skin —> hair follicles
- germ cells —> embryo
- bone marrow —> immune system
Pathological aspects of chemotherapy-induced N+V
Medullary Chemoreceptor trigger zone (CTZ) / Vomiting centre:
—> **D2 receptor + **5HT-3 receptor
- Directly activated by chemotherapy
- Peripherally in GI tract —> Serotonin —> CTZ
Peripheral pathway:
- activated within 24 hours after initiation of chemotherapy
- drugs cause cell damage in GI tract
—> induce Enterochromaffin cells release Serotonin (EPAN pathway)
—> activate **5-HT3 receptors
—> dorsal root / cranial nerve afferent
—> CNS
—> Nausea, vomiting and abdominal pain
—> **5HT3 antagonist (Gold standard, e.g. Ondansetron)
—> block peripheral + CNS 5-HT3 receptors
—> Advantage: Long duration of action, administered as single dose prior to chemotherapy
Central pathway:
- located primarily in brain
- delayed chemotherapy-induced emesis
- activated after 24 hours
- Vagus nerve
—> **Substance P
—> activate **NK-1 receptor (Neurokinin-1)
—> ***NK-1 receptor antagonists
Other NT:
- Dopamine
- Endocannabinoids
Other problems associated with chemotherapy
- Resistance (inherited / acquired —> acquired mutation)
- minimised by **short-term, **intensive, ***intermittent therapy with combinations of drugs - Multidrug resistance (MDR)
- stepwise selection of an amplified gene that codes for a transmembrane protein, ***P-glycoprotein
- ATP-dependent pumping of drug out of tumour cell by P-glycoprotein - Treatment induced tumours
- May arise >=10 years after original cancer cured (∵ most drugs are mutagens, esp. after therapy with ***alkylating agents)
***Advantages of drug combinations
- Higher response rate (∵ additive / ***potentiation of cytotoxic effects but non-overlapping host toxicity)
- Provide **maximal cell killing within the range of **tolerated toxicity
- Effective against ***broader range of cell lines in heterogeneous tumour population
- Delay / prevent development of ***resistant cell lines
- Agents with similar ***dose-dependent toxicities can be combined safely by reducing doses of each drug (e.g. Myelosuppression, Nephrotoxicity, Cardiotoxicity)
Example:
CHOP:
1. Cyclophosphamide (Alkylating agent)
2. Doxorubicin (Topoisomerase II inhibitor)
3. Vincristine (Anti-microtubule)
4. Prednisolone
***Classification and Actions of chemotherapeutic drugs
General MOA:
Macromolecular synthesis / function
—> Interfere with DNA, RNA, Protein synthesis (e.g. purine / pyrimidine availability)
—> Cytotoxic effect / Apoptosis
Classification based on cell-cycle specificity:
Cell-cycle specific drugs:
1. Antimetabolites (S phase)
2. Mitotic inhibitors (M phase)
3. Topoisomerase inhibitors (S phase)
—> Effective for High-growth-fraction malignancy e.g. leukaemia
—> Greatest effect: Continuous infusion / Divided doses with short cycle
Cell-cycle non-specific drugs (act on all phases of cell cycle —> does not differentiate between normal / malignant cell, cytotoxic effect likely involve >1 mechanisms, multiple intracellular site affected, given bolus):
1. Alkylating agents
2. Anti-tumour antibiotics
3. Hormone antagonists
4. Monoclonal Ab
—> Effective for both High + Low-growth-fraction malignancy e.g. solid tumours
Combination:
—> Cell-cycle non-specific drugs recruit cells into more actively-dividing state
—> make it more sensitive to Cell-cycle specific drugs
Classification based on MOA:
1. Cytotoxic drugs
- Antimetabolites (interfere with formation of key biomolecules e.g. nucleotides)
- Plant derivatives (vinca alkaloids, taxanes, campothecins —> specifically affect microtubule function —> inhibit formation of mitotic spindle)
- Alkylating agents (forming covalent bonds with DNA —> impede replication)
- Cytotoxic antibiotics (substances of microbial origin —> prevent mammalian cell division)
- Hormones / Steroids
- Glucocorticoid
- Estrogen
- Androgen
- Drugs that suppress hormone secretion / antagonise hormone action - Miscellaneous agents
- do not fit above categories
- recently developed drugs designed to affect specific tumour-related targets
Life cycle of cell
G0 (resting, non-dividing)
—> G1 (synthesis of enzymes needed for DNA synthesis)
—> S (DNA replication)
—> G2 (synthesis of cellular components required for mitosis)
—> M (mitosis, formation of 2 identical daughter cells)
Mitotic spindle: condensed mass of microtubules and proteins that control movement of chromosome during mitosis
Mitosis:
1. Prophase:
- chromatin condenses
- mitotic spindle begins to form
- nucleolus disappears
- Prometaphase:
- discrete chromosomes appear
- spindle attach to chromosome
- nuclear envelope fragments - Metaphase:
- spindle completed
- chromosomes aligned in centre of cell - Anaphase:
- chromatids separate
- daughter chromosomes moving to opposite end - Telophase:
- daughter nuclei forming
- cytokinesis begins
Antimetabolites
Cell-cycle specific
—> Maximal cytotoxic effects in ***S-phase
- Synthetic products structurally related to Purines, Pyrimidines, Folates (endogenous metabolites) required for DNA / RNA synthesis
- Interfere with availability of normal purine / pyrimidine nucleotide precursors
- inhibit synthesis of nucleotide precursors
OR
- competing with nucleotide precursors in DNA/RNA synthesis
—> cells cannot carry out vital function with fake building blocks
—> cell death
Drugs:
1. Methotrexate
2. Purine antagonist (6-Mercaptopurine / 6-Thioguanine)
3. Pyrimidine antagonist (5-Fluorouracil)
***Methotrexate
Folate antagonist (structurally ~B9)
MOA:
Block active site of **DHFR (dihydrofolate reductase)
—> Folate cannot be reduced to THF (active form)
—> inhibit **Nucleotide (Adenine, Guanine, Thymidine) + ***Amino acid production (Methionine, Serine)
THF: co-enzyme needed for methylation —> deliver methyl groups (one-carbon unit) to specific target molecules (used to form nucleotides)
(MTX polyglutamated in cell (like THF) —> intracellular retention of MTX)
***Leucovorin / Folinic acid:
- administered along with MTX to prevent excessive toxicity of MTX towards normal cells (reduced folate: bypass inhibited DHFR)
- active form of folate
- sufficiently stable to be produced and marketed
Therapeutic use:
- Combination with other drugs for Acute lymphocytic leukaemia, Burkitt’s lymphoma, Breast cancer, Head and neck carcinoma etc.
- Other use (anti-inflammatory): RA, Psoriasis, Crohn’s
Pharmacokinetics:
- Oral, SC, IV, IM, Intrathecal
- Renal excretion mostly unchanged drug
- High doses MTX —> hydroxylation —> 7-hydroxyMTX —> Crystalluria (less water soluble)
- Avoid ***Renal toxicity: keep urine alkaline + patient well-hydrated
(SE:
- **Hepatotoxicity
- Ulcerative stomatitis / Mucositis
- Leukopenia
- **Pneumonitis / Pulmonary fibrosis
- ***Teratogenic)
***Purine antagonists
- 6-Mercaptopurine (~Adenine) (**Thio (多左個Thio group) analogue of Hypoxanthine / Thiopurine) —> **Azathioprine (prodrug of 6-MP)
- 6-Thioguanine (~Guanine)
**MOA x3:
6-MP:
converted to Nucleotide analogue TIMP (6-thioinosinic acid / 6-MP-ribose phosphate) (by HPRT)
1. **TIMP inhibits **de novo purine ring biosynthesis (by acting on PRPP amidotransferase, IMP dehydrogenase)
2. TIMP block **formation of AMP and XMP (subsequently GMP) from IMP
3. TIMP converted to ***TGMP (6-TG) —> RNA/DNA containing TGMP are non-functional
Pharmacokinetics:
- Oral / IV (high dose)
- Bioavailability reduced by 1st pass metabolism in liver
—> **TPMT: methylation of 6-MP —> 6-MMP
—> **Xanthine oxidase: 6-MP —> 6-thiouric acid
Therapeutic use:
- Maintainance of remission in Acute lymphoblastic leukaemia
- Acute leukaemia
- Paediatric non-Hodgkin’s lymphoma
- Azathioprine: ***Immunosuppressive therapy (Crohn’s disease, transplantation, glomerulonephritis)
6-MP pharmacokinetics
6-MP
- Metabolic activation:
—(HPRT)—> TIMP —> TGMP / 6-TG (non-functional nucleotide) - Metabolic inactivation:
—(TPMT)—> 6-MMP
—(Xanthine oxidase)—> 6-thiouracil —> 6-thiouric acid
6-MP adverse effects
***Myelosuppression
Subjects with ***defective TPMT (should be tested for TPMT polymorphism)
—> greatly ↑ risk for life-threatening myelosuppression when treated with “standard dose”
—> ↓ dose 10-15 fold in TPMT poor metabolisers
***Allopurinol (XO inhibitor) (also used to counter hyperuricemia in cancer treatment)
—> ↓ 6-MP dose 75% —> avoid accumulation of 6-MP
(SE:
- **Hepatotoxicity
- GI upsets
- **Pancreatitis
- Leukopenia
- Anaemia
- Thrombocytopenia)
Pyrimidine antagonists
- 5-Fluorouracil (5-FU) (多左個Fluoro group)
- Cytosine arabinoside
- Gemcitabine
- Cepecitabine
MOA:
5-FU
—> 5-FUMP (nucleotide fluorouridine monophosphate)
—> **5-FdUMP —> **inhibit Thymidylate synthase (TMS) —> inhibit pyrimidine nucleotide formation —> inhibit DNA synthesis (dUMP —X—> dTMP —> DNA)
OR
—> **5-FUTP —> **incorporated in DNA/RNA —> interfere DNA synthesis
***Leucovorin co-administration:
Cytotoxic activity potentiated by co-administration of Leucovorin calcium
—> Leucovorin required in Thymidylate synthase inhibition
—> increased effectiveness of 5-FU to inhibit TMS
Pharmacokinetics:
- IV (most common)
- Intra-arterial infusion (into hepatic artery through implanted pump)
- **Topically (skin cancer)
- penetrate well into all tissues, diffuse readily across BBB, distribute into CSF / brain tissue
- metabolised extensively in **liver
- excreted by kidneys, lungs
Therapeutic use:
- wide spectrum of solid tumours (breast cancer, pancreatic cancer etc.)
- applied to skin via a cream to treat ***Actinic keratosis, Basal cell carcinoma due to chronic prolonged sun exposure —> used as preventative measure
***Mitotic inhibitors
Mitotic inhibitors:
- affect equilibrium between polymerised and depolymerised microtubules
—> Cell-cycle specific + Phase specific:
—> ***M-phase active, some activity in G2, S phases
Drugs:
1. Vinca alkaloids (Vincristine, Vinblastine, Vinorelbine)
2. Taxanes (Paclitaxel, Docetaxel)
(Mitotic spindle: consists of microtubules formed by Tubulin —> essential for equal partitioning of DNA into daughter cells)
- Vinca alkaloids
Extracts of Vinca rosea
Drugs:
1. Vincristine (VX)
2. Vinblastine (VBL)
3. Vinorelbine (VRB, newer, less toxic)
MOA:
- **GTP-dependent binding to Tubulin
—> **prevent polymerisation to form microtubules
—> dysfunctional spindle in metaphase
—> prevent chromosomal segregation and cell proliferation
Pharmacokinetics:
- drug resistance due to **efflux via P-glycoprotein
- **CYP450 (concentrated and metabolised)
—> Must be modified in impaired hepatic function
SE:
- **Myelosuppression (Vinblastine more potent than Vincristine)
- **Peripheral neuropathy (Vincristine)
- Granulocytopenia (Dose limiting factor for Vinorelbine)
Therapeutic use of Vinca alkaloids (Similar structures but different indications):
- Vincristine: Leukaemia (POMP regimen), Hodgkin’s lymphoma (MOPP regimen)
- Vinblastine: Metastatic Testicular carcinoma (administered with Bleomycin, Cisplatin)
- Vinorelbine: Advanced non-small cell lung cancer (as single agent / with Cisplatin)
- Taxanes
Drugs:
1. Paclitaxel (1st drug, isolated from Yew tree, one of most active anti-cancer drugs)
2. Docetaxel (semisynthetic analogue of Paclitaxel, more water soluble and potent than Paclitaxel)
MOA:
Bind reversibly to **Tubulin
—> **promote polymerisation and stabilisation
—> fail to depolymerise
—> ***accumulation of non-functional microtubules
—> chromosomes cannot segregate
—> frozen in metaphase
Pharmacokinetics:
- drug resistance: P-glycoprotein / Tubulin mutation
- long t1/2
- substantial hepatic metabolism (CYP450)
- biliary excretion
- large volume of distribution
- IV
Therapeutic use:
- Advanced ovarian cancer (in combination with Cisplatin)
- Metastatic breast cancer
- Non-small (Large) cell lung cancer
- Small cell lung cancer (Paclitaxel)
- Karposi’s sarcoma (Paclitaxel)
- Prostate, Gastric cancer (Docetaxel)
SE:
Paclitaxel:
- pre-medicated with Dexamethasone, Diphenhydramine, H1+H2 blocker due to serious hypersensitivity reactions
- **Neutropenia, Myelosuppression, Alopecia, **Neuropathy, Mouth sores, Allergic reactions, N+V, diarrhoea
Docetaxel:
- **CI in cardiac disease
- **Neutropenia, hypersensitivity, **fluid retention (↑ capillary permeability), skin (rash, desquamation of hands, feet, onychodystrophy, palmar-plantar erythrodysesthesia that may respond to Pyridoxine / Cooling), Neuropathy, asthenia
—> Post-medication: **Corticosteroids for fluid retention
***Topoisomerase inhibitors
Topoisomerase enzymes:
- unwind and wind DNA to facilitate DNA replication
- regulate how tightly packed is DNA, dynamic state of torsional energy during DNA replication
- induce either transient DNA single-strand breaks (Topoisomerase 1) / DNA double-strand breaks (Topoisomerase 2)
- expressed in highly proliferative cells
Drugs (plant-derived):
1. Topoisomerase 1 inhibitors (derived from Camptothecin):
- Irinotecan
- Topotecan
- Topoisomerase 2 inhibitors (derived from Podophyllotoxin):
- Etoposide
- Teniposide
Topoisomerase 1 inhibitors
Irinotecan, Topotecan: semisynthetic derivatives of Camptothecin (unpredictable toxicity)
MOA:
Stabilise Topo 1-DNA complex
—> **prevent re-winding of single-strand breaks created by enzyme
—> converted to **permanent double-strand breaks
—> ***S-phase specific
Therapeutic use:
- Topotecan: Metastatic ovarian cancer (when primary therapy failed), SCLC
- Irinotecan: 1st line for Colorectal carcinoma (together with 5-FU, Leucovorin)
Topoisomerase 2 inhibitors
Etoposide, Teniposide: semisynthetic derivative of Podophyllotoxin
MOA:
Bind to Topo 2-DNA complex
—> **stabilisation of Topo 2-DNA intermediate
—> **prevent re-winding of double-strand breaks / initial DNA cleavage
—> persistent, cleavable Topo 2-DNA intermediate
—> **irreversible breaks in double strands of DNA (protein-linked)
—> inhibit DNA synthesis (cells do not enter mitosis / prophase)
—> **G2, S-phase specific
Therapeutic use:
- Oat-cell carcinoma of lung
- Testicular carcinoma (combination with Bleomycin, Cisplatin)
- 2nd line in treatment of Acute lymphocytic leukaemia (Teniposide)
(Topoisomerase 2:
Topo 2 binds non-covalently to gate (G) duplex
—> Topo2-G duplex bind at crossover region with transported (T) duplex
—> **ATP bind and promote formation of Topo 2-DNA intermediate
—> **Mg-dependent cleavage of G duplex
—> T duplex (unbroken) pass through gap formed in G duplex
—> G duplex re-ligated and bound ATP is hydrolysed)
Alkylating agents
Alkylation: Replacing Hydrogen by Alkyl group
MOA:
- Alkylating agents form highly reactive **electrophilic species (i.e. electron deficient)
—> Alkyl group covalently bind onto nucleophilic sites (i.e. electron excess) of cellular macromolecules (e.g. DNA bases, Protein)
—> Alkyl group attached to **Guanine base of DNA (at number 7 nitrogen atom of imidazole ring)
—> **Abnormal base pairing, **DNA breakage, ***Cross-linking
Adverse effect:
- Mutagenic, Carcinogenic (potentially lead to second malignancy)
Drugs:
1. Nitrogen mustards
- Cyclophosphamide, Ifosfamide, Chlorambucil, Melphalan
- Nitrosoureas
- Carmustine, Lomustine - Cisplatin
Cyclophosphamide and Ifosfamide
Cyclophosphamide: most commonly used alkylating agent
Cyclophosphamide and Ifosfamide:
- Pro-drugs —> converted to active toxic form (Phosphoramide mustard) in cancer cells
MOA:
**Hydroxylation by CYP450
—> **Phosphoramide mustard (active compound)
—> Alkylation of DNA
Pharmacokinetics:
- Oral (Cyclophosphamide only)
- IV (Cyclophosphamide, Ifosfamide)
- well-distributed through body (brain, CSF)
SE:
- Myelosuppression
- ***Haemorrhagic cystitis —> lead to bladder fibrosis (∵ Acrolein)
—> adequate hydration, IV Mesna (sodium mercaptoethanesulfonate) neutralise Acrolein
Therapeutic use:
- wide variety of neoplastic diseases (single / combination)
Nitrosoureas (Carmustine, Lomustine, Fotemustine)
Highly lipophilic / lipid soluble alkylating agents
—> widely distribute in body, penetrate CNS
Therapeutic use:
- ***Brain tumours (∵ penetrate CNS)
Cisplatin
Heavy metal platinum complex
MOA:
Platinum atom of Cisplatin binds covalently to N7 position of Guanine
—> produce **Intra (1,2 / 1,3) + **Inter-strand linkages in DNA through covalent bonds
—> formation of ***Cisplatin-DNA adducts
—> Replication arrest, Transcription inhibition, Cell-cycle arrest, DNA repair, Apoptosis
Therapeutic use:
- Almost every solid tumours and lymphoma
- Synergistic cytotoxicity in combination with radiotherapy / other chemotherapy
Pharmacokinetics:
- metabolised in liver
- excreted in urine —> Nephrotoxicity
SE:
- **Nephrotoxicity (dose-related) —> aggressive hydration
- severe N+V —> Pre-medication with Anti-emetic required
- **Ototoxicity —> high frequency loss, tetanus
Anti-tumour antibiotics
- Mostly isolated from fermented broths of various Streptomyces bacteria
- Cell-cycle nonspecific
- some considered Topo-2 inhibitors because they induce double stranded DNA breaks
—> Doxorubicin, Daunorubicin, Idarubicin
MOA:
Interact with DNA
—> disrupt DNA function
Drugs:
Anthracyclines
- Doxorubicin (DOX)
- Daunorubicin (DNR)
- Epirubicin
- Idarubicin
Doxorubicin
MOA:
1. **Intercalating between base pairs of DNA/RNA
2. Inhibit **Topo-2 enzyme —> prevent relaxation of supercoiled DNA
3. Interact with oxygen —> ***superoxide ions, H2O2 —> single-strand breaks in DNA
Pharmacokinetics:
- IV (∵ inactivated in GI tract)
- extensive ***hepatic metabolism
- biliary excretion
- do not penetrate BBB
Therapeutic use (combination with other agents):
- Sarcoma
- Variety of carcinoma
- Acute lymphocytic leukaemia
- Lymphomas
SE:
- **Cardiotoxicity (irreversible, dose-dependent) (result of free radicals, lipid peroxidation)
—> Iron-chelator **Dexrazoxane protect against cardiotoxicity
- Extravasation —> Tissue necrosis
Hormones and Hormone antagonists
Steroid hormone-sensitive tumours:
1. Hormone responsive (regress after treatment with a hormone)
2. Hormone dependent (regress after removal of hormonal stimulus)
—> can be accomplished by surgery (e.g. orchiectomy with advanced prostate cancer) / drugs
3. Both
MOA:
Block endogenous substances that stimulate tumour growth
Drugs:
1. Corticosteroid
2. Androgen
3. Estrogen
4. Progestin
5. Anti-androgen
6. Anti-estrogen (Tamoxifen)
7. Gonadotropin inhibitors
8. Aromatase inhibitors
Tamoxifen
- Anti-estrogen
- Selective estrogen receptor modulator (SERM) —> weak estrogenic effect at various sites
- Agonist at other sites (e.g. bone, endometrium) —> endometrial cancer
MOA:
Bind to Estrogen receptors in target cells
—> Estrogen unavailable to tumour
—> **cannot activate gene transcription
—> **inhibit Estrogen-induced growth of breast cancer
—> suppress action of Estrogen / other growth factors
SE:
- Hot flushes, vaginal bleeding/discharge
Long term SE:
- **Endometrial cancer
- **Thromboembolic events (stroke, pulmonary embolism)
- Cataract
Therapeutic use:
- 1st line in ***Estrogen receptor-positive breast cancer
- Prevention of breast cancer in high risk women
- only approved for 5 years of use
Targeted therapy
- Drugs that interfere with ***specific molecules involved in carcinogenesis
—> block growth and spread of cancer - Many focus on proteins involved in signalling process
- May be more effective than current treatments, ***Fewer SE (∵ less harmful to normal cells)
Anti-cancer targets for selective toxicity
1. Altered metabolic enzyme (L-asparaginase to kill cells that cannot synthesise asparagine)
2. **Cell surface receptors (Trastuzumab (Herceptin) blocks **HER2 receptor in breast cancer)
3. Altered **biological process e.g. **Angiogenesis (Bevacizumab, VEGFR inhibitor)
4. Altered ***intracellular signalling (Imatinib target Abl kinase which is turned on in chronic myelocytic leukaemia)
Use of Ab:
1. Recruit natural effectors (ADCC)
2. Neutralise growth factors (VEGF)
3. Block receptor / signal transduction
4. Stimulate apoptotic signalling
Trastuzumab (Herceptin)
Humanised monoclonal Ab
—> only Ag binding region (CDRs) from rat
—> other components from human
HER-2/neu gene (erbB-2):
- encodes for ***human epidermal growth factor receptor type 2 (HER-2)
- amplified in up to 30% of breast cancers
- stimulate cell proliferation —> more aggressive tumour
MOA:
Trastuzumab targets extracellular domain of HER2 growth receptor
—> inhibit proliferation of cells that overexpress HER2 protein by ***ADCC
Pharmacokinetics:
- IV
- does not penetrate BBB
SE:
- ***Congestive heart failure (worsen when taken with Anthracyclines)
Therapeutic use:
- Breast cancer (administered with Paclitaxel)
***Summary of drugs
Cell-cycle specific drugs:
1. Antimetabolites
- Methotrexate —> Nephrotoxicity, Leucovorin
- Purine antagonist (6-MP / Azathioprine) —> TPMT, Allopurinol, Myelosupression
- Pyrimidine antagonist (5-FU) —> Leucovorin, Topical for skin cancer
- Mitotic inhibitors
- Vinca alkaloids (Vincristine, Vinblastine, Vinorelbine) —> prevent Tubulin polymerisation to form microtubules, Myelosuppression, Peripheral neuropathy
- Taxanes (Paclitaxel, Docetaxel) —> stabilise microtubules then fail to depolymerise, Neutropenia, Fluid retention - Topoisomerase inhibitors
- Topo 1 inhibitors (Irinotecan, Topotecan)
- Topo 2 inhibitors (Etoposide, Teniposide)
Cell-cycle non-specific drugs:
1. Alkylating agents —> Carcinogenic
- Nitrogen mustard (Cyclophosphamide, Ifosfasmide) —> Haemorrhagic cystitis
- Nitrosoureas (Carmustine, Lomustine) —> Highly lipophilic for Brain tumours
- Cisplatin —> Nephrotoxicity, Ototoxicity
- Anti-tumour antibiotics
- Anthracyclines (Doxorubicin, Daunorubicin) —> Cardiotoxicity, Iron chelator Dexrazoxane - Hormone antagonists
- Anti-estrogen / SERM (Tamoxifen) —> Endometrial cancer, Thromboembolic events - Monoclonal Ab
- HER2 receptor antagonist (Trastuzumab) —> Congestive heart failure
