Cancer Chemotherapy & Pharmacology Flashcards
Cancer
= uncontrolled growth and spread within the body of abnormal forms the body’s own cells.
Cancer cells
- uncontrolled proliferation
- de-differentiation
- immature
- loss of function
- ‘immortal’ - Invasiveness
- actively leave tissue of origin - Metastasis
- can proliferate in foreign tissues
Chemotherapy
Chemotherapy = drugs that are selectively toxic to the invading organism (or cancer) but harmless or having minimal effects on the host (or normal cells)
Goal of chemotherapy is aimed at near total cancer cell kill Used in conjunction with surgery and radiotherapy
Anti-cancer drug classes: cytotoxic agents (DNA)
Alkylating
Antimetabolites
Cytotoxic antibodies
Plant derivatives and similar compounds
Anti-cancer drug classes: hormonal
Hormones/antagonists
- disrupt hormone dependent tumour growth
Anti-cancer drug classes: non-cytotoxic
Protein kinase inhibitors
Monoclonal antibodies
Cytotoxic drugs: Alkylating agents
Eg. Cyclophosphamide, cisplatin, dacarbazine, ifosfamide, melphalan
Form intra-strand covalent bonds in DNA
- impedes transcription & replication
- induces apotosis
Cyclophosphamide uses
Use:
• Strong effects on lymphocytes
• Anti-cancer drug and immunosuppressant
lymphoma, breast cancer, leukemia, myeloma
• One of most commonly used alkylating agents • Given orally or i.v.
• Inactive until metabolized by P450 in liver
Cyclophosphamide side effects
immune suppression, carcinogenic,
bone marrow toxicity (myelosuppression), GIT lining damage, nausea/vomiting, haemorrhagic cystitis (bladder), alopecia
Cytotoxic drugs: Antimetabolites
Eg. Methotrexate, 5-fluorouracil, mercaptopurine, cytarabine
Block metabolic pathways involved in DNA / RNA synthesis
Methotrexate
• Folate is essential for synthesis of purine nucleotides (building blocks of DNA/RNA)
• Inhibits dihydrofolate reductase
=> inhibits production of purines/pyrimidines
Methotrexate uses and side effects
Use:
• Orally (also i.m., i.v., i.t.) • Anticancer:-
Breast and lung cancer, leukemia, lymphoma • Immunosuppressant (Rheumatoid Arthritis)
Side effects: Bone marrow toxicity (myelosuppression), GIT lining damage, nausea/vomiting, pulmonary and liver toxicity, hair loss (alopecia)
Cytotoxic drugs: Cytotoxic antibiotics
Eg. Doxorubicin, mitomycin, dactinomycin, epirubicin
From microbes (Streptomyces spp.), too toxic as antibiotic drugs Prevent cell division via multiple effects on DNA/RNA synthesis - Bind to DNA and/or - inhibit topoisomerase enzyme
Doxorubicin mechanism
- Topoisomerase II inhibitor (DNA gyrase)
- Binds to DNA (between base pairs)
- Traps DNA bound topoisomerase II
Doxorubicin use
- Given i.v. (possible necrosis at injection site)
- Broad use for solid and blood tumours
- Not given with radiotherapy (cumulative toxicity)
Doxorubicin side effects
myelosuppression, nausea/vomiting, hair loss (alopecia), cardiotoxicity (high doses)
Non cytotoxic drugs 1: Antibodies
Antibody mechanisms
neutralise and flag invaders for destruction
Inhibit growth factors or GF receptors
- Bind to agonist or receptor (inhibition)
- Increase receptor internalisation
- complement-dependent cytotoxicity 2. anti-body-dependent cell-mediated cytotoxicity (ADCC) via TC (CTL) cells
Antibodies: Herceptin
HER2 is an oncogenic growth factor receptor (human epidermal growth factor receptor 2)
• Expressed breast cancer cells in ~25% breast cancer patients (aggressive form)
• Often used in combination with a taxane (e.g. docetaxel)
Herceptin mechanisms
Mechanism A. Prevents receptor activation B. Induces anti-body- dependent, cell mediated cytotoxicity (ADCC) C. Enhances receptor internalization => decreases receptor active number
Herceptin side effects
Side effects:
Hypotension, chills / fever, GI disturbances, fatigue, may induce hypersensitivity reactions
Possible liver and cardio toxicity
Non-Cytotoxic drugs 2: Tyrosine kinase inhibitors
e.g imatinib
Inhibit protein kinases involved in growth factor receptor signaling => Targeted therapeutics (= lower side effects than cytotoxics)
Imatinib - uses and SE
- inhibits oncogenic cytoplasmic kinase (Bcr/Abl)
- Unique oncogene in chronic myeloid leukemia (CML)
- Also inhibits kinase of platelet derived growth factor
Use:
• Given orally for CML • Some GIT tumors
Side effects: GIT disturbances (pain, diarrhoea), nausea, headaches, fatigue, ~rashes
Hormonal anti-cancer drugs: (non-cytotoxic 3)
E.g Tamoxifen (anti oestrogen);
Used in hormone-dependent tumors (breast, uterus, prostate) Þ Hormone receptors expressed in malignant cells
1: Suppress hormone synthesis/secretion
2: Antagonise hormone action
Tamoxifen mechanism
Mechanism:
• Competes with endogenous oestrogen in breast cells (not in bone or endometrium)
• Inhibits transcription of oestrogen-dependent genes • Decreases expression of some growth factors
Tamoxifen use and SE
Use:
• Effective in some hormone-dependent breast cancers
• May be preventative (used in high risk women)
Beneficial side effects:
• lowers LDL cholesterol => Risk of heart disease
• Strengthens bones
• Reduces breast cancer risk
Side effects: similar to menopause
Increase uterine cancer risk, and blood clot risk
Tamoxifen problems
Resistance
already be resistant or develop resistance to effects of anti-cancer drugs
- Kinetic changes: uptake / metabolism
(e. g. cyclophosphamide) - Dynamic changes: enzyme
(e. g. methotrexate) - Induction of multiple drug resistance (MDR1) gene (P-glycoprotein / abc transp.)
(e. g. Doxorubicin)
Limited efficacy
Single drugs can have varied effectiveness in many cancers
Combination therapy
- produces synergistic cell kill => increase efficacy (r.r.)
- decreases development of resistance
- decreases side effects
Guide for combinations
• Have some efficacy when used alone
• Drugs with different limiting side effects
• Use drugs with different mechanisms of action
anti Cancer drugs side effects
Nausea and vomiting:
Major side effect from many anti-cancer drugs Common reason for decreased patient compliance
Myelosuppression: bone marrow toxicity
Major limiting side effect of many anti-cancer drugs
Results in low blood cell counts (anemia/fatigue, fever, bruising, susc inf.) - neutropenia
Side effect management
Side effect management
Combination therapy:
Can increase cytotoxic effects on cancers without increasing s.e.
Dosing regimes: larger doses with 2-3 week gaps =>
1: allows bone marrow to recover
2: can get more effective cell kill than more frequent small doses
Pharmacological management:
Nausea and vomiting can be controlled using 5-HT3 receptor antagonists (ondansetron or granisetron) or metoclopramide Folinic acid: used with high doses of methotrexate
G-CSFs
SUMMARY
• Cytotoxics = more side effects, and more severe
• Targeted therapies = less side effects, very expensive
• Problems include lack of efficacy, resistance and side effects
• Nausea and vomiting = big problems for seeing cycles completed.
• Combination therapy, different dosing regimes and pharmacological management
helps get around several of the problems.
