Cancer Chemotherapy

What is cancer?

Uncontrolled multiplication and spread within the body of abnormal forms of the body's own cells

What is a neoplasm?

A mass of tissue formed as a result of abnormal, excessive, uncoordinated, autonomous, and purposeless proliferation of cells

What are the 4 basic characteristics of all cancers?

Uncontrolled proliferation, invasive growth, tendency to metastasize, and changes in morphology of the original cell

What are the three treatment approaches for cancer?

Surgery, radiotherapy, and chemotherapy

How does chemotherapy work?

Systemically administers drugs that directly damage cellular DNA and RNA, killing cells by promoting apoptosis and sometimes necrosis

What does chemotherapy exploit about cancer cells?

The accelerated rate of cell division in cancerous cells compared to normal cells

Why is there a narrow therapeutic window in chemotherapy?

Drugs are not cancer-specific — they damage all rapidly dividing cells including normal tissues

What are the three chemotherapeutic techniques?

Cytotoxic therapy, endocrine therapy, and immunotherapy

What is the ultimate goal of cancer chemotherapy?

Cure — long-term disease-free survival requiring eradication of every neoplastic cell

What is the goal when cure is unattainable?

Control — prevent enlargement and spread to extend survival and maintain quality of life

What do most cytotoxic drugs affect?

DNA synthesis

Against which cells are cytotoxic drugs most active?

Proliferating cells — both normal and malignant

What is the difference between phase-specific and cycle non-specific drugs?

Phase-specific drugs kill only during specific cell cycle phases; cycle non-specific drugs kill cells throughout the entire cell cycle

Why do cytotoxic drugs have relative selectivity for cancer over normal cells?

A higher proportion of tumour cells are proliferating at any time AND normal cells recover from chemotherapy damage faster than cancer cells

What is the log kill hypothesis?

Chemotherapeutic agents kill a constant fraction of cells per dose (first-order kinetics) rather than a constant number

Why is 100% cell kill difficult to achieve?

Due to fractional kill kinetics, minimal immune participation, early symptom disappearance, and pharmacological sanctuaries

What are pharmacological sanctuaries?

Tissues like the CNS where some chemotherapeutic agents cannot enter due to transport constraints — allowing tumour cells to survive

How can pharmacological sanctuaries be overcome?

By radiation, surgery, or intrathecal drug administration

What are the two types of chemotherapy resistance?

Primary resistance — no response on first exposure; acquired resistance — develops during treatment

What is P-glycoprotein and why is it important in chemotherapy resistance?

A membrane efflux pump that protects cells against toxins — when overexpressed in cancer cells, it pumps out chemotherapy drugs causing multidrug resistance

Name six mechanisms of chemotherapy resistance

Decreased drug uptake, increased drug efflux via P-glycoprotein, altered target sensitivity, rapid repair of DNA lesions, insufficient drug activation or increased inactivation, increased target enzyme concentration

Which cancers are examples of the decreased drug uptake resistance mechanism?

Methotrexate resistance

Which drugs are affected by P-glycoprotein efflux resistance?

Vinblastine, doxorubicin, and bleomycin

Which anticancer drugs have the highest risk of causing secondary treatment-induced tumours?

Alkylating agents, topoisomerase inhibitors, and anthracyclines

What normal tissues are most damaged by cytotoxic chemotherapy?

Bone marrow, GI epithelium, hair follicles, reproductive organs — all high growth fraction tissues

What is myelosuppression and how is it managed?

Suppression of bone marrow activity — managed with colony stimulating factors or bone marrow replacement before and after chemotherapy

What reproductive effects do cytotoxic agents cause?

Oligospermia, impotence, and decreased ovulation in adults; abortion, foetal death, and teratogenicity in the foetus

What are the three types of chemotherapy-induced nausea and vomiting?

Acute (peaks 4–6 hours post-treatment), delayed (after 24 hours), and anticipatory (conditioned response from previous cycles)

What drug class is first-line for chemotherapy-induced nausea and vomiting?

5-HT₃ antagonists — Ondansetron, Granisetron, Tropisetron, Palonosetron

Name a Neurokinin-1 receptor antagonist used for CINV

Aprepitant or Fosaprepitant

What is used for anticipatory emesis?

Behavioural therapy combined with benzodiazepines

What glucocorticoid is used as an antiemetic in chemotherapy?

Dexamethasone

What is the rationale for combination chemotherapy?

Using cytotoxics with different mechanisms of action AND different toxicity profiles to increase cytotoxicity, reduce general toxicity, and decrease resistance

Give an example of a rational drug combination in chemotherapy and explain why

Methotrexate (myelosuppression) + Vincristine (neurotoxicity) — different toxicities allow full doses without compounding one adverse effect

In which cancers can monotherapy be adequate?

Burkitt's lymphoma and choriocarcinoma

Why are cisplatin and bleomycin preferred combination partners?

They have low myelotoxicity — they don't compound bone marrow suppression from other agents

What is an intermittent regimen in chemotherapy?

Drugs given in large doses over several courses with 2–3 week intervals to allow normal host cells to regenerate and recover

What is pulse therapy?

A type of intermittent regime employing the highest tolerated dose within a short administration period

What are the three major groups of antineoplastic agents?

Cytotoxic drugs, hormones and hormone antagonists, and immunotherapy

Where was the discovery of Vinca alkaloids serendipitous?

Researchers were exploring anti-diabetic claims of Madagascar periwinkle (Catharanthus roseus) and discovered granulocytopenia in rats

Name the four active alkaloids from Catharanthus roseus

Vinblastine, Vincristine, Vinleurosine, and Vinrosidine

What is the mechanism of action of Vinca alkaloids?

Bind to β-tubulin and block polymerisation with α-tubulin into microtubules — preventing mitotic spindle formation — arresting mitosis in M-phase

Are Vinca alkaloids phase-specific or cycle non-specific?

Phase-specific — M-phase

What is the key difference in microtubule effect between Vinca alkaloids and Taxanes?

Vinca alkaloids block polymerisation (spindle cannot form); Taxanes block depolymerisation (spindle forms but cannot break down)

What are the clinical uses of Vincristine?

Paediatric leukaemias, lymphomas, Wilms' tumour, neuroblastoma, and rhabdomyosarcoma

What are the clinical uses of Vinblastine?

Bladder cancer, testicular carcinomas, Hodgkin's disease, Kaposi's sarcoma, neuroblastoma

What is Vinorelbine used for?

Non-small cell lung cancer and breast cancer

What are the adverse effects of Vinca alkaloids?

Peripheral neuropathy (numbness, tingling, loss of reflexes, motor weakness), fatal central neurotoxicity (seizures, irreversible coma), and severe constipation (especially Vincristine)

What is the source of Taxanes?

First isolated from the bark of the Pacific Yew tree (Taxus brevifolia) in 1971, later from European Yew (Taxus baccata)

Name two Taxane drugs

Paclitaxel and Docetaxel

What is the mechanism of action of Taxanes?

Promote microtubule polymerisation and inhibit depolymerisation — stabilizing polymerized microtubules — arresting cells in mitosis and activating apoptosis

How does Paclitaxel induce apoptosis beyond microtubule stabilization?

Binds to Bcl-2 (an anti-apoptotic protein), arresting its function and allowing apoptosis to proceed

What causes hypersensitivity reactions with Paclitaxel?

The solvent cremophor used to dissolve the drug

How are Taxane hypersensitivity reactions prevented?

Pretreatment with an antihistamine and dexamethasone (glucocorticoid)

What are the clinical uses of Docetaxel?

Metastatic ovarian, breast, lung, and head and neck cancers — plus significant activity against hormone-refractory prostate cancer

What is the source of Camptothecin analogues?

Chinese tree Camptotheca accuminata

Name two Camptothecin analogues

Irinotecan and Topotecan

What is the mechanism of action of Camptothecin analogues?

Inhibit Topoisomerase I — stabilizing the transient DNA-Topoisomerase I complex — accumulating single-strand DNA breaks — collision with replication fork causes irreversible double-strand breaks and cell death

Are Camptothecin analogues phase-specific?

Yes — S-phase specific

What are the adverse effects of Irinotecan?

Diarrhoea, thrombocytopenia, and cholinergic side effects

What is the source of Epipodophyllotoxins?

Podophyllotoxin — a glycoside from the root of the mandrake plant (Podophyllum peltatum)

Name two Epipodophyllotoxin drugs

Etoposide and Teniposide

What is the mechanism of action of Etoposide?

Forms a complex with Topoisomerase II and DNA — preventing resealing of the DNA break normally following topoisomerase binding

What is Teniposide specifically indicated for?

Refractory ALL in children

What are cytotoxic antibiotics?

Substances of microbial origin that prevent mammalian cell division by modifying DNA within cancer cells

Name four cytotoxic antibiotics

Anthracyclines (Doxorubicin, Daunorubicin), Bleomycin, Dactinomycin (Actinomycin D), Mitomycin C

What is the mechanism of action of Anthracyclines?

DNA intercalation causing local uncoiling and blockade of DNA and RNA synthesis; inhibition of Topoisomerase II; and free radical generation producing superoxide and hydrogen peroxide causing single-strand DNA scission

What is the classic dose-dependent toxicity of Anthracyclines?

Cardiotoxicity — cumulative dose-dependent cardiomyopathy

What is the mechanism of Bleomycin?

Forms DNA-Bleomycin-Fe²⁺ complex → oxidized to Fe³⁺ → electrons react with O₂ → hydroxyl/superoxide radicals → attack phosphodiester bonds → strand breakage and chromosomal aberrations

What makes Bleomycin unique among cytotoxic antibiotics?

Very little myelosuppression — making it a preferred combination partner

What organ does Bleomycin characteristically damage?

The lungs — pulmonary toxicity (pneumonitis/fibrosis)

What is Dactinomycin and what is its mechanism?

Actinomycin D — a polypeptide antibiotic from Streptomyces sp. that intercalates DNA and inhibits transcription and mRNA synthesis — cell cycle phase NON-specific

What is the clinical use of Dactinomycin?

Limited to gestational and paediatric tumours

What is the source of Mitomycin C?

Streptomyces caespitosus

What is the mechanism of Mitomycin C?

Alkylates DNA, inhibits DNA synthesis, and cross-links DNA base pairs causing strand breakage; at higher concentrations also inhibits RNA and protein synthesis

What haematological effect does Mitomycin C preferentially cause?

Prolonged myelosuppression preferentially affecting platelets and leukocytes

What is the principle behind hormonal therapy in cancer?

Some neoplasms depend on specific hormones for growth — blocking or reducing hormone action inhibits tumour growth

What is the primary hormonal treatment for distant metastases in prostate cancer?

Anti-androgen therapy

Name two GnRH antagonists used in prostate cancer

Nafarelin and Triptorelin

Name two androgen receptor antagonists used in prostate cancer

Bicalutamide and Flutamide

Why do prostatic tumours eventually become resistant to androgen deprivation?

Loss or mutation of the androgen receptor

What plasma marker is used to assess response to anti-androgen therapy?

Prostate-Specific Antigen (PSA)

What is the difference between SERMs and SERDs?

SERMs competitively bind the estrogen receptor with mixed agonist/antagonist effects depending on the organ; SERDs bind and downregulate/degrade the receptor with NO agonist activity anywhere

Name three SERMs used in breast cancer

Tamoxifen, Raloxifene, Toremifene

Name two SERDs used in breast cancer

Fulvestrant and Elacestrant

What is the mechanism of Aromatase inhibitors?

Inhibit aromatase enzyme — blocking conversion of androgens (androstenedione, testosterone) to estrogens (estrone, estradiol) in multiple tissues

Name two Aromatase inhibitors

Anastrozole and Letrozole (reversible competitive inhibitors)

What are the adverse effects of estrogen inhibitors?

Hot flushes, hair thinning, vaginal bleeding, menstrual irregularities, venous thromboembolism, asthenia

What are the antineoplastic mechanisms of Glucocorticoids?

Inhibition of angiogenesis by downregulating VEGF and IL-8; inhibition of autocrine growth factor in multiple myeloma

What supportive roles do Glucocorticoids play in oncology?

Reducing raised intracranial pressure from cerebral metastases and mitigating chemotherapy-induced nausea and vomiting

What is the mechanism of L-asparaginase?

Hydrolyses circulating L-asparagine to aspartic acid and ammonia — depriving lymphoid malignant cells (which cannot synthesize their own asparagine) of the amino acid needed for protein synthesis

Why are normal cells unaffected by L-asparaginase?

Normal cells can synthesize their own L-asparagine — they do not depend on plasma asparagine

What is the clinical use of L-asparaginase?

Acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma — in combination therapy

What is the mechanism of Hydroxyurea?

Inhibits ribonucleoside diphosphate reductase — blocking the rate-limiting conversion of ribonucleotides to deoxyribonucleotides required for DNA synthesis

What is Hydroxyurea used for?

Myeloproliferative syndromes — CML and polycythemia vera

What is the mechanism of Protein Tyrosine Kinase Inhibitors?

Inhibit abnormally activated protein tyrosine kinases that drive neoplastic proliferation — causing cell death through apoptosis

Name three Protein Tyrosine Kinase Inhibitors

Imatinib, Gefitinib, Erlotinib

What are Protein Tyrosine Kinase Inhibitors used for?

CML, gastrointestinal stromal tumours, dermatofibrosarcoma

What is the history of Thalidomide in oncology?

Originally used for pregnancy morning sickness — withdrawn due to teratogenicity and dysmelia — reintroduced for cancer due to antiangiogenic and immunomodulatory effects

What are the mechanisms of IMIDs like Thalidomide?

Stimulation of T cells and NK cells, inhibition of angiogenesis and tumour cell proliferation, modulation of haematopoietic stem cell differentiation