February 14, 2013

Today, we will be discussing the cell cycle and how it affects tissue growth and regrowth.  We will also touch on some basic mechanisms of chemotherapy drug resistance.

• Cell cycle kinetics

1.      DNA synthesis does not occur continuously through cell cycle, but only during the S-phase.

2.      Total cell cycle time for normal human tissue is 1-2 days, while most malignant cells take 2-3 days.  Cell cycle kinetics do not adequately describe tumor growth.

• Phases of the cell cycle (the cell cycle is important because most chemotherapeutic drugs work against actively reproducing cells).

1.      G1 phase:  during this phase, the cell starts making more proteins and growing larger, so the new cells will be of normal size.  This phase lasts about 18 to 30 hours.

2.      S phase:  in the S phase, the chromosomes containing the genetic code (DNA) are copied so that both of the new cells formed will have matching strands of DNA. The S phase lasts about 18 to 20 hours.

3.      G2 phase:  in the G2 phase, the cell checks the DNA and gets ready to start splitting into 2 cells.  This phase lasts from 2 to 10 hours.

4.      M phase (mitosis):  in this phase, which lasts only 30 to 60 minutes, the cell actually splits into 2 new cells.

5.      G0 (resting stage):  the cell has not yet started to divide.  Cells spend much of their lives in this phase. G0 can last from a few hours to a few years.  When the cell gets a signal to reproduce, it moves in to the G1 phase.  Cells in G0 often act as a reserve population which can re-enter the pool of proliferating cells and repopulate a tissue.

• Tissue growth kinetics

1.      Proliferating cells are in minority; most cells are in G0, are no longer capable of replicating, or are dead.

2.      Most tumors have a low growth fraction and a high rate of cell loss.

3.      Most daughter cells don’t survive due to inherent genetic instability.

4.      Tumors often outstrip their vascular supply and develop large areas of necrosis.

5.      Most tumors are not what they appear to be – seething masses of rapidly dividing cells.

6.      Yet, tumor growth is progressive because the homeostatic mechanisms are malfunctioning thus allowing unlimited cell repopulation.

7.      For a large portion of a tumor’s life it grows exponentially.

8.      Using Gompertzian equations, it is estimated that most malignancies originate less than two years prior to clinical detection.

9.      The most effective use of chemotherapy is on tumors low on the Gompertzian growth curve (or cells which are actively proliferating at a high rate), so debulking large tumors to move it down on the curve (so G0 cells re-activate) prior to chemo is a beneficial clinical practice.

• Stem cell model of tumor growth

1.      Proliferating cells (most vulnerable to chemo) aren’t necessarily the cells that must be eliminated to eradicate a tumor; the critical population is those cells in G0.

2.      Response to of a tumor to a drug is best assessed by measuring the survival of the clonogenic (stem) cells, not of all tumor cells.

• Tumor cell survival & dosing

1.      The relationship is exponential meaning that multiple courses of chemo are needed to eradicate the tumor and small changes in the dose translate into large changes in cell survival.

2.      Reduction in dose is often unavoidable because of undue toxicity to normal tissues, but giving drugs in full doses (amount and frequency) is always the goal in treatment planning.

• Mechanisms of drug resistance

1.      Sometimes tumors are inaccessible to most drugs (CNS and testes for example).

2.      Some drugs promote resistance to themselves.

3.      Often developing resistance to one chemo drug results in resistance to other drugs (even structurally unrelated ones).

4.      The most typical explanation for drug resistance, however , is the genetic/biochemical makeup of malignant cells (spontaneous mutation)

5.      Tumors are genetically diverse and have high mutation rates, and some chemo drugs may increase the instability of these tumor cells by acting as mutagens themselves, and drug-resistant clones replace the sensitive ones over a treatment course.

Reflections:

As a radiation therapist, many of my patients will be receiving adjuvant chemotherapy.  I know that they will be weak and tired from their treatments because their bodies will be in overdrive trying to repair all of the damage done to them by the chemotherapy and the radiation therapy.  I will be able to recommend to them to be eating a high calorie diet along with large amounts of protein so that the body can have the energy and amino acids to fix problems within the stem cells that are getting damaged. 

I will also know that as chemotherapy is administered that drug resistance might occur because of cell mutations.