Cancer Chemotherapy and Adjuvant Therapy

Cancer Chemotherapy

• Cancer chemotherapy involves the use of drugs to treat cancer, with the goal of killing cancer cells while minimizing harm to normal cells.
• Ideal chemotherapy would kill all cancer cells, but in practice, the goal is to kill all growing cells.

Drug Classification

• Cell Cycle Specific Agents: Kill cancer cells in a specific phase of the cell cycle.
  • Examples: Antimetabolites, Bleomycin, Podophyllin alkaloids, Vinca alkaloids
• Cell Cycle Nonspecific Agents: Kill cancer cells regardless of the cell cycle phase.
  • Examples: Alkylating Agents, Antibiotics (e.g., Actinomycin), Cisplatin, Nitrosoureas

Mechanisms of Action

• Alkylating Agents:
  • Mechanism of action: Mono- and bifunctional; form covalent bonds with nucleophilic groups in proteins and nucleic acids.
  • Examples: Nitrogen mustards, Nitrosoureas, Methane sulfonate esters, Ethyleneimines
• Antimetabolites:
  • Mechanism of action: Interfere with nucleic acid biosynthesis.
  • Examples: Folic acid analogs (e.g., Methotrexate), Purine analogs (e.g., 6-Mercaptopurine), Pyrimidine analogs (e.g., 5-Fluorouracil)
• Microtubule Inhibitors:
  • Mechanism of action: Interfere with microtubule function, preventing cell division.
  • Examples: Vinca alkaloids, Taxanes (e.g., Paclitaxel, Docetaxel)
• Chromatin Function Inhibitors:
  • Mechanism of action: Inhibit topoisomerase enzymes, leading to DNA damage.
  • Examples: Podophyllotoxins (e.g., Etoposide, Teniposide), Camptothecins

Resistance to Chemotherapy

• Mechanisms of Resistance:
  • Decreased drug uptake
  • Increased drug inactivation
  • Mutations in activating enzymes
  • Increased drug extrusion
  • Multidrug resistance (MDR) due to p-glycoprotein

Host Determinants

• General Health Status:
  • Ability to tolerate drugs and side effects
  • Nutritional state
  • Infections
  • Renal and bone marrow function
• Immune Status:
  • Natural antitumor defense mechanisms (e.g., macrophages, T cells, NK cells)
• Site of Tumor and Blood Supply:
  • Tumor location and blood supply affect chemotherapy delivery and efficacy

Targeted Therapy

• Definition: Therapy that targets specific molecules required for tumor development and growth.
• Examples:
  • Monoclonal antibodies (e.g., Rituximab, Trastuzumab)
  • Signal transduction inhibitors (e.g., Gefitinib)
  • Receptor inhibitors (e.g., Panitumumab, Cetuximab)
  • Aromatase inhibitors (e.g., Letrozole)

Adjuvant Therapy

• Definition: Use of chemotherapy in addition to surgery or radiation therapy to treat cancer.

• Goal: To eliminate any remaining cancer cells and prevent recurrence.### Kinetics of Killing

• The goal of Cancer Chemotherapy Treatment (CCT) is to kill as many tumor cells as possible while minimizing harm to normal cells, achieving tumor regression, increased patient survival time, and alleviation of symptoms.

Selective Toxicity

• CCT faces a challenge due to only quantitative differences between normal and neoplastic cells, resulting in non-selective treatment and differences in growth rate.

Immune System

• The immune system responds minimally to tumors, which are not recognized as different, and can be overwhelmed by them, highlighting the need for total cell kill in CCT since a single malignant cell can give rise to sufficient progeny to kill the host.

Kinetics

• First-order kinetics are characterized by each regimen of CT killing a constant percentage (log kill) of cells.
• Effective CCT can achieve a 3 log kill, reducing 10^12 cells to 10^9 cells.

Tumor Cell Killing

• The tumor burden is composed of 10^12 cells, which can be reduced to a new steady state of 10^9 cells with effective CCT.
• The larger the tumor, the harder it is to kill, due to factors such as poor vascularization, non-proliferating cells, and increased incidence of metastasis.

Total Tumor Burden (Size)

• A clinically detectable tumor consists of 10^9 cells (1 cm), while lethal tumors can have 10^12 cells.
• The time required for CCT increases with the size of the tumor.