The key variable is the fraction of cycling cells, not the speed of the cycle
Tumor cells are not necessarily faster than normal cells; they are more numerous in the actively cycling compartment. The growth fraction — the proportion of cells in cycle rather than in G0 — is the main determinant of how many cells a cycle-dependent drug can reach.
Growth fraction across tissues
High growth fraction
- Bone marrow (hematopoietic precursors)
- Gut epithelium (crypt cells)
- Hair follicle matrix
- Many aggressive tumors
Low growth fraction
- Liver (hepatocytes)
- Kidney (tubular epithelium)
- Most connective tissue
- Some slow-growing tumors
Why phase-specific drugs need prolonged exposure
A phase-specific drug can only kill a cell that is in its target phase at the moment the drug is present. At any instant, only a fraction of cycling cells occupy that phase — for example, S phase typically lasts a few hours out of a cycle that may take a day or more. A single short exposure therefore misses most cells. Prolonged infusion or repeated dosing keeps the drug present long enough for a larger fraction of the cycling population to pass through the sensitive phase. This is also why phase-specific drugs are more effective against tumors with a high growth fraction: more cells enter the sensitive phase per unit time.
Predicting vulnerable normal tissues
If a patient receives a phase-specific S-phase drug, which normal tissues will show toxicity first? The tissues with the highest growth fractions — bone marrow, gut epithelium, and hair follicles — because their cells are constantly entering S phase. A tissue like liver, with a low growth fraction, will show little acute toxicity from an S-phase-specific agent even though the drug is present in the blood. This prediction matches the clinical pattern of myelosuppression, mucositis, and alopecia seen with antimetabolites.