In principle, chemotherapeutic drugs are able to treat cancer and spare normal cells by exploiting inherent differences in their individual growth patterns. Each tumor type has its own characteristics, which explains why the same chemotherapy regimen is not equally effective for the whole spectrum of gynecologic cancers. Selecting appropriate drugs and limiting toxicity demands an understanding of cellular kinetics and biochemistry.
All dividing cells follow the same basic sequence for replication. The cell generation time is the time required to complete the five phases of the cell cycle (Fig. 27-1). The G1 phase (G = gap) involves various cellular activities, such as protein synthesis, RNA synthesis, and DNA repair. When this is prolonged, the cell is considered to be in the G0 phase, that is, the resting phase. G1 cells may either terminally differentiate into the G0 phase or reenter the cell cycle after a period of quiescence. During the S phase, new DNA is synthesized. The G2 (premitotic) phase is characterized by cells having twice the DNA content as they prepare for division. Finally, actual mitosis and chromosomal division take place during the M phase.
Diagram of the cell cycle. Agents are organized according to the cell cycle stage in which they are most effective for tumor control.
Tumors do not typically have faster generation times. They instead have many more cells in the active phases of replication and have dysfunctional apoptosis (programmed cell death). In contrast, normal tissues have a much larger number of cells in the G0 phase. As a result, cancer cells proceeding through the cell cycle may be more sensitive to chemotherapeutic agents, whereas normal cells in G0 are protected. This growth pattern disparity underlies the effectiveness of chemotherapeutic agents.
Tumors are characterized by a gompertzian growth pattern. Namely, a tumor mass requires progressively longer times to double in size as it enlarges. When a cancer is microscopic and nonpalpable, growth is exponential. However, as a tumor enlarges, the number of its cells undergoing replication decreases due to limitations in blood supply and increasing interstitial pressure.
When tumors are in the exponential phase of gompertzian growth, they should be more sensitive to chemotherapy because a larger percentage of cells are in the active phase of the cell cycle. For this reason, metastases should be more sensitive to chemotherapy than a large primary tumor. To capitalize on this potential benefit, advanced ovarian cancer is usually first treated with surgery to remove the primary tumor, debulk large masses, and leave only microscopic residual disease for the adjuvant chemotherapy to act on. In addition, when a tumor mass shrinks in response to ...