Table 2.

Many clinically impactful chemotherapeutic agents are pro-drugs and rely on cancer-specific biotransformation for specific killing.

Representative example (class)	Structure of Administered Drug (pro-drug)	Active Agent (bio-transformed)	Mode of action	Mechanism of selectivity	Reference
Cyclophosphamide (Nitrogen mustards)			DNA damage through crosslinking	Loss of ALDH1A1 in de-differentiated cancer cells, basic tumor intracellular	[32]
Temozolomide (Triazenes)			DNA damage through methylation	MGMT silencing, cytosolic alkaline pH in GBM	[33]
5-fluorouracil (Nucleotide analogue)			DNA, RNA damage, Inhibition of TS	Overexpression of enzymes of thymidine phosphate synthesis	[34]
Irinotecan (Topoisomerase Inhibitors)			Topoisomerase inhibition leads to DNA breakage	Butyrylcholine Esterase activity, overexpressed in cancer cells	[35]
Cisplatin (Platinum agents)			DNA damage: crosslinking	Aquation due to more alkaline intracellular and lower intracellular chloride	[36]
Methotrexate (Anti-folates)			Anti-folate: inhibition of nucleotide synthesis	Increased import via overexpressed folate receptor and trapping by polyglutamylation in cancer	[37]

^*A representative panel of clinically useful conventional chemotherapies is shown. Combined treatment with one or more agents shown is responsible for curing a substantial number of cancer patients. Pro-drug moieties which undergo biological removal are indicated in red; those which undergo biological addition are indicated in magenta. Mechanisms outlined for each example are applicable for the broader class that it represents; for example, all nucleotide analogues require biotransformation to their monophosphate forms for bioactivity.