Tumour resistance to cisplatin: a modelling approach

Area of Science:

• Oncology
• Pharmacology
• Mathematical Biology

Background:

• Chemotherapy, while effective for hematological tumors, shows limited success in solid tumors due to factors like drug resistance and poor understanding of pharmacokinetics.
• Cisplatin is a key cytotoxic agent for head and neck cancers, but its efficacy can be compromised by resistance mechanisms.
• Generalized chemotherapy models involve numerous assumptions; modeling cisplatin as a single agent simplifies analysis.

Purpose of the Study:

• To develop a computational model simulating the biological effects of cisplatin on head and neck squamous cell carcinoma.
• To investigate the impact of cisplatin resistance on tumor control by simulating various resistance mechanisms.
• To quantify drug resistance using a defined cisplatin resistance factor (CRF).

Main Methods:

• Utilized computer-based Monte Carlo techniques to simulate tumor growth, incorporating stem, proliferating, and non-proliferating cells.
• Modeled cisplatin's biological effect and simulated resistance using a cisplatin resistance factor (CRF).
• Conducted a sensitivity study on mechanisms contributing to drug resistance.

Main Results:

• Demonstrated a supra-linear relationship between CRF and the percentage of cisplatin-DNA adducts formed.
• Observed a sigmoid-like dependence between CRF and the percentage of cells killed in resistant tumors.
• Indicated that drug resistance is a cumulative process that can ultimately lead to treatment failure.

Conclusions:

• Cisplatin resistance significantly impacts treatment outcomes in head and neck cancers.
• The developed model provides insights into the complex interplay between cisplatin, DNA adducts, cell kill, and resistance.
• Understanding and overcoming cisplatin resistance is crucial for improving therapeutic success in solid tumors.