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)
