Principles of cancer chemotherapy – Pharmacology

What are the 3 main approaches to cancer treatment?

Surgery; Radiotherapy; Chemotherapy (drug therapy)

What are the types of cancer chemotherapy?

Palliative chemotherapy; Adjuvant chemotherapy; Neoadjuvant chemotherapy; Chemoprevention

What is palliative chemotherapy?

Chemotherapy primarily used for patients with metastasis; goal is symptom improvement and quality of life; survival increments are secondary; treatment should minimise adverse effects and be well tolerated

What is adjuvant chemotherapy?

Chemotherapy given after initial cytoreductive intervention to eradicate remaining micrometastatic disease and improve disease-free and overall survival

What is neoadjuvant chemotherapy?

Chemotherapy administered before a planned cytoreductive procedure to reduce surgery requirements, increase successful debulking, reduce hospitalisation, and improve patient fitness

What is chemoprevention?

Use of pharmacological agents to prevent cancer development in high-risk patients; agents should modify risk without significant adverse effects

How are anticancer chemotherapeutic agents broadly classified?

Cytotoxic agents; Hormonal therapy; Kinase inhibitors; Monoclonal antibodies; Miscellaneous agents

What are the major classes of cytotoxic agents?

Alkylating agents; Antimetabolites; Cytotoxic antibiotics; Plant derivatives

What are the subclasses of alkylating agents discussed in the lecture?

Nitrogen mustard (cyclophosphamide); Nitrosourea (carmustine); Platinum compounds (cisplatin)

What are the subclasses of antimetabolites discussed in the lecture?

Folate antagonists (methotrexate); Pyrimidine pathway antagonists (fluorouracil); Purine pathway antagonists (6-mercaptopurine)

What are the anticancer antibiotics discussed in the lecture?

Doxorubicin and bleomycin

What are the plant derivatives discussed in the lecture?

Taxanes (paclitaxel, docetaxel); Vinca alkaloids (vincristine, vinblastine); Etoposide

What hormonal therapies are discussed in the lecture?

Glucocorticoids, GnRH analogues, estrogens, progestogens, antiestrogens, antiandrogens, aromatase inhibitors

Which alkylating agents are cell cycle non-specific (CCNS)?

Alkylating agents are cell cycle non-specific drugs

What is the general mechanism of action of alkylating agents?

Intra-strand cross-linking of DNA; interferes with transcription and DNA replication; inhibits DNA synthesis and function

How does cyclophosphamide exert its cytotoxic effect?

Reacts with guanosine moieties in DNA causing cross-linking, mismatch, and damage leading to cytotoxic effects

What are the therapeutic uses of cyclophosphamide?

Chronic lymphocytic leukaemia; Hodgkin’s lymphoma; non-Hodgkin’s lymphoma; solid tumours; RA with severe systematic manifestations (unlicensed indication)

What metabolite causes cyclophosphamide-induced haemorrhagic cystitis?

Acrolein

What is the specific toxicity of cyclophosphamide?

Haemorrhagic cystitis caused by acrolein metabolite

How does mesna reduce cyclophosphamide toxicity?

Mesna binds to acrolein and reduces toxicity

How can cyclophosphamide-induced haemorrhagic cystitis be ameliorated?

Increased fluid intake and administration of sulfhydryl donors such as N-acetylcysteine or mesna

What are the general adverse effects of cyclophosphamide?

Bone marrow suppression; nausea; vomiting; decreased spermatogenesis; increased incidence of acute leukaemia with prolonged treatment especially with radiotherapy

What is the MOA of carmustine?

Same as cyclophosphamide (DNA alkylation and cross-linking)

Why is carmustine useful for brain tumours?

Lipid soluble and crosses the blood-brain barrier

What is the main use of carmustine?

Brain cancers and tumours of the brain and meninges

What is the most common adverse effect of carmustine?

Bone marrow suppression

What are the adverse effects of carmustine?

Bone marrow suppression; reduced spermatogenesis; severe rash that may lead to Stevens-Johnson syndrome

What is the mechanism of action of platinum compounds?

Cross-link complementary DNA strands causing cross-linking mismatch damage and cytotoxicity

Are platinum compounds cell cycle specific?

No, they are not cell-cycle specific

What is the main platinum compound discussed in the lecture?

Cisplatin

What are the therapeutic uses of cisplatin?

Germ cell tumour; bladder cancer; lung cancer; upper GI cancer; ovarian cancer

What is the most important dose-limiting toxicity of cisplatin?

Serious dose-related nephrotoxicity

What supportive measures are necessary with cisplatin therapy?

Strict regimens of hydration and diuresis

What antiemetic is very effective for cisplatin-induced nausea and vomiting?

Ondansetron (5-HT3 receptor antagonist)

What are the adverse effects of cisplatin?

Nephrotoxicity; bone marrow toxicity; severe nausea and vomiting; ototoxicity; hypomagnesaemia

What are folates essential for?

Synthesis of purine nucleotides and thymidylate, which are essential for DNA synthesis and cell division

What is methotrexate?

One of the most widely used antimetabolites in cancer chemotherapy

What is the mechanism of action of methotrexate?

Inhibits DHFR enzyme and depletes intracellular FH4

What cancers is methotrexate used to treat?

Breast cancer; head and neck cancer; osteogenic sarcoma

What non-cancer conditions can methotrexate be used for?

Rheumatoid arthritis; psoriasis; other autoimmune conditions

What are the adverse effects of methotrexate?

Bone marrow depression; gastrointestinal epithelial damage; pneumonitis

What rescue therapy is required after high-dose methotrexate?

Folinic acid rescue

What is the mechanism of action of fluorouracil?

Interferes with dTMP synthesis by interacting with thymidylate synthetase resulting in inhibition of DNA synthesis

What is the most widely used indication for fluorouracil?

Colorectal cancer

What other cancers can fluorouracil treat?

A wide variety of solid tumours

What are the main adverse effects of fluorouracil?

Gastrointestinal epithelial damage and myelotoxicity

What is the mechanism of action of 6-mercaptopurine?

HGPT enzyme converts 6-MP to compounds that inhibit new formation of ribosyl-5-phosphate, inhibit formation of adenine and guanine nucleotides, induce strand breaks and base mispairing

What does HGPT stand for?

Hypoxanthine guanine phosphoribosyl transferase

What is the principal use of 6-mercaptopurine?

Leukaemias

What is the major adverse effect of 6-mercaptopurine?

Myelosuppression

What is the significance of low erythrocyte TPMT activity in patients receiving 6-mercaptopurine?

Associated with increased drug toxicity and lower risk of relapse

What is the mechanism of action of doxorubicin?

Inhibits DNA synthesis by inhibition of topoisomerase II (DNA gyrase)

Why is topoisomerase II an important target in cancer therapy?

Its activity is markedly increased in rapidly proliferating cells

How does doxorubicin affect the DNA-topoisomerase II complex?

Intercalates into DNA and stabilises the DNA-topoisomerase II complex after DNA strands are nicked, halting replication processes

What are the therapeutic uses of doxorubicin?

Breast cancer; lymphoma; solid tumours

What are the adverse effects of doxorubicin?

Cardiotoxicity; alopecia; myelosuppression; stomatitis

What is the mechanism of action of bleomycin?

Degrades preformed DNA causing DNA chain fragmentation and acts on non-dividing cells

What is the therapeutic use of bleomycin?

Germ line cancers

What is the most serious toxic effect of bleomycin?

Pulmonary fibrosis

How much myelosuppression does bleomycin cause?

Little myelosuppression

What is the mechanism of action of taxanes such as paclitaxel?

Act on microtubules as mitotic spindle poisons by stabilising (freezing) them in the polymerised state, inhibiting mitosis and cell division

What is the mechanism of action of vinca alkaloids?

Inhibition of tubulin polymerisation causing disruption of microtubule assembly, mitotic arrest in metaphase, and cell death

What are the vinca alkaloids discussed in the lecture?

Vincristine and vinblastine

What is the most important use of vinblastine?

Metastatic testicular tumours

What is the treatment of choice role of vincristine?

With glucocorticoids for childhood leukaemias; also used in paediatric solid tumours and lymphomas

What are the uses of vincristine?

Leukaemia and various haematologic malignancies

What are the adverse effects of vincristine?

Peripheral neuropathy; neurotoxicity; myelosuppression; alopecia

What are the uses of paclitaxel?

Ovarian cancer; breast cancer; NSCLC; SCLC; broad range of solid tumours

What are the adverse effects of paclitaxel?

Myelosuppression and peripheral sensory neuropathy

What is the mechanism of action of etoposide?

Inhibition of topoisomerase II resulting in DNA damage

What are the adverse effects of etoposide?

Alopecia and myelosuppression

How do glucocorticoids act as anticancer agents?

Markedly inhibit lymphocyte proliferation

What cancers are glucocorticoids used to treat?

Leukaemias and lymphomas

How do GnRH analogues act in cancer therapy?

Inhibit gonadotrophin release

What are the uses of GnRH analogues such as leuprolide?

Advanced breast cancer in premenopausal women and prostate cancer

What is the use of diethylstilbestrol?

Palliative treatment of androgen-dependent prostatic tumours

What is the use of medroxyprogesterone?

Endometrial cancer

What is the mechanism of action of tamoxifen?

Competes with endogenous oestrogens for oestrogen receptors and inhibits transcription of oestrogen-responsive genes

What is the main use of tamoxifen?

Hormone-dependent breast cancer

What important adverse effect can occur with long-term tamoxifen use?

Endometrial carcinoma

What is the use of flutamide?

Treatment of androgen-dependent prostate tumours

How do aromatase inhibitors work?

Suppress synthesis of oestrogen from androgens in the adrenal cortex

Name two aromatase inhibitors discussed in the lecture.

Anastrozole and letrozole

What is the clinical use of aromatase inhibitors?

Breast cancer treatment in postmenopausal women

What are kinase inhibitors?

Small-molecule inhibitors of signalling pathway kinases representing a conceptual breakthrough in targeted chemotherapy

What is the mechanism of action of imatinib?

Inhibits an oncogenic cytoplasmic kinase involved in the pathogenesis of chronic myeloid leukaemia

What disease prognosis has been greatly improved by imatinib?

Chronic myeloid leukaemia

What is the general mechanism of action of monoclonal antibodies in cancer therapy?

Attach to and inactivate growth factors or their receptors, inhibit survival pathways, promote apoptosis, activate host immune mechanisms, and induce complement-mediated lysis or killer T-cell killing

What is a major advantage of monoclonal antibodies?

Highly targeted therapy with fewer side effects than conventional chemotherapy

What is a major limitation of monoclonal antibodies?

High cost

What is the target of rituximab?

CD20

How does rituximab work?

Binds CD20 on B lymphocytes and activates complement causing lysis

What is the use of rituximab?

Certain types of lymphoma in combination with other chemotherapeutic agents

What is the target of bevacizumab?

VEGF

How does bevacizumab work?

Neutralises VEGF and prevents angiogenesis crucial for tumour survival

What is the use of bevacizumab?

Colorectal cancer

What is the target of trastuzumab?

HER2 (human epidermal growth factor receptor 2)

How does trastuzumab work?

Humanised murine monoclonal antibody that binds HER2 receptor on tumour cells

In what proportion of breast cancer patients is HER2 overexpressed?

About 25%

What is the clinical significance of HER2 overexpression?

Associated with rapidly proliferating aggressive breast cancer