Cytotoxic drugs damage the reproductive potential of cells by acting on DNA ❌. Selectivity depends on ❌ of synthesis/division:
• ❌ dividing cells more likely to respond to Tx
• ❌ cancer cells resistant

Cell-cycle phase❌ drugs: schedule dependent (time dependent)
Cell-cycle phase-❌ drugs: dose dependent

Growth fraction is number of cells in ❌ over the total number of cells. This is normally ❌%. It changes in cancers eg Burkitt’s lymphoma: 100% GF, Colon carcinoma: <5%.
Greater growth fraction means a ❌ chance of cell death.
The ❌ is the proportion of cells a cytotoxic dose kills. Note that drugs kill a proportion of cells, not a given number of cells. Intermittent therapy ❌ tumour cell killing and allows ❌ of healthy cells.

Toxicity related to cytotoxic drugs:
The therapeutic index is a measurement of the relative ❌ of a drug, usually around 1(below one is less safe). It is a comparison of the amount of a therapeutic agent that causes the therapeutic ❌, to the amount that causes ❌.
In cancer a therapeutic dose is a ❌ dose.
The drug action is ❌ to the growth rate; meaning a greater effect in ❌ growth fraction & vice versa.
The drug with affect ❌ dividing (cancerous AND non-malignant) tissue.

Match the tissues to their types of proliferation.

Continuous rapid proliferation - ❌ marrow, ❌ mucosa, ❌ follicles, ❌ germ cells
Continuous slow proliferation - ❌ epithelium, ❌ endothelium
Cyclical proliferation - Glandular female ❌ tissue, ❌ lining of uterus
Capacity to proliferate after injury - ❌
Non proliferating - ❌ Cartilage

Hematopoietic system toxicity:
Bone marrow suppression occurs when ❌ cell pool is damaged by chemotherapy. Clinically we see a ❌ in circulating cells. Platelets gone within ❌ weeks. Granulocytes within 14 days. Fall in white cell count by ❌ days. No change in RBCs for ❌ weeks. Then, bone marrow ❌ occurs.

(Erythrocyte life span: ❌ days. Platelet: ❌ days. WBCs: ❌ days.)

Nearly all cytotoxics cause BM suppression at therapeutic doses but severity and duration ❌. Why?
1. Different effects on ❌ stem cells (pluripotent vs unipotent)
2. Kinetics of cell types in peripheral blood (❌ of cells)
3. Cycle nonspecific drugs: greater ❌ than phase specific

Low BMS with ❌.
Cancer cells have ❌ [hydrolase], BM cells have ❌ [hydrolase].

Nausea and vomiting as a SE has a complex mechanism, only partly due to ❌ action of drugs on GIT. It can affect the ❌ nerve which affects the ❌ centre. Anticipatory nausea is common and the pathway uses ❌.

GI Tract toxicity:
Observed as oesophagitis, diffuse ileitis, colitis, oral ❌.
• Mucosal cells have ❌ turnover (4-7 days)
• ❌ after cytotoxic administration: Pain, tingling, dryness, loss of taste - - - ❌
• Consider the combo of ❌ trauma/low ❌ count/pathogen ❌ environment
• Severity: dose related, schedule of administration
• Worse in ❌ people.

Dermatological toxicity:
1. Alopecia
• ❌ hair follicles actively dividing, 24h doubling time
• ❌
2. Specific skin toxicity (uncommon)
• ❌: Palmar-plantar syndrome (redness, swelling, and ❌ on palms and soles). Affects growth of skin cells, capillaries
3. Extravasation

Match the cytotoxics to the cell phase they act in.
G1 - ❌
S phase - ❌
G2 - ❌
Mitosis - ❌
Phase non-specific - ❌ agents, Cytotoxic ❌, ❌-based drugs

Alkylating agents:
❌ binding to 1) DNA - blocks DNA/RNA ❌ and 2) proteins - blocks DNA ❌.
Cell-cycle ❌.
Causes ❌ suppression, hair loss, GI disturbances.
PK depends on structure.

e.g. ❌ for breast and bronchi cancer. Hydroxylation in liver makes the active ❌. Risks: Haemorrhagic cystitis (stay ❌), ❌ damage (with high dose).

Cytotoxic antibiotics:
Anthracyclines (Streptomyces): e.g. Daunorubicin, ❌, epirubicin
In general - cell cycle ❌ specific.
• DNA intercalation
• Inhibits ❌
• Blocks ❌, disrupt normal replication = cell death
Poor gut absorbtion so given ❌.
Toxicitity:
❌ – dose dependent and cumulative
Maximum ❌ dose recommended to prevent heart failure.

Special case: Bleomycin. Non-anthracycline cytotoxic AB for ❌ tumours, Hodgkin’s ❌.
Mode: DNA intercalation, free radical-induced ❌ (cell cycle ❌).
Pulmonary and dermatological toxicity, low BM suppression: pulmonary ❌ (partially reversible), ❌(50% of patients).

Platinum compounds e.g. cisplatin, carboplatin, oxaliplatin. AKA ‘Non-classical alkylating agents’.
MoA: ❌ interact with ❌ - INTRA strand ❌-linking.
❌ infusion, excreted by ❌. Long t1/2: ❌h, due to protein binding.
◦ BM suppression and GI toxiciity - requires ❌ support
◦ Renal toxicity (❌)
◦ ❌, tinnitus, hearing loss
◦ Peripheral neuropathy

Antimetabolites:
• Structural similarity to ❌ of normal metabolism
• Incorporation into nucleic acids e.g. ❌ (prodrug)
• Enzyme substrates that inhibit RNA and DNA ❌
• Good ❌ absorption, also IV, intrathecal
• ❌ excretion

e.g. Methotrexate (MTX) for leukaemias (breast, head, lung and neck).
• ❌ analogue, stops ❌ synthesis
Toxicity: BM (leukocytes) – infection, GI (mucosa)

Mitotic inhibitors which are ❌ derivatives are cell cycle-specific.

1. Vinca alkaloids
e.g. Vincristine, vinblastine, vindesine, vinorelbine
Bind to ❌, inhibits polymerisation (mitosis). Eliminated via metabolism. Given ❌ usually. Toxicity: constipation, BMS usually dose limiting (absent for ❌), dose-limiting ❌ for vincristine, neuropathy (mixed motor/sensory), paraesthesia, loss of deep reflexes (axonal transport).

2. Taxanes
e.g. Docetaxel, paclitaxel
Stabilise ❌ structure, prevent cell division. Poor ❌ absorbtion. Hepatic metabolism. Toxicity: Dose-limiting ❌, arthralgia/myalgia syndrome (mechanism unknown)
Paclitaxel: ❌ neuropathy (motor at higher dose)
Docetaxel: leg ❌ (fluid retention – peripheral effect)