DNA Review
Remember DNA is a double helical structure. It has the chromosomes that direct cellular life. So replication takes place as the DNA is a template. The DNA is also a template for the messenger RNA which goes to the ribosomes. Then the transfer RNA codons have to match up and each 3 codons that match up make up an amino acid. So as a result, proteins can be created. The bottom line is that the drugs we’re concerned with affect one or more of these processes and that’s how these cancer cells are going to be killed.
- Double helix structure
- Chromosomes that direct cellular life
- Directs formation of RNA
- Protein synthesis dependent on mRNA and tRNA
- Each 3 codons make up an amino acid
- Chemotherapy can block synthesis
Cancer Cell Cycle
We’re going to break the process of the cancer cell cycle into two phases. There’s more phases than this but we’re just going to discuss these. The S phase is where replication and activity takes place. Remember how we said the only way to kill bacteria is for when it’s growing? The only way we could kill a cancer cell is if it’s growing. If it’s dormant and not growing, we can’t kill it. So these medications are S-phase and it’s the only place they could work. The G0 phase (referred to the G zero phase) is the non replicating phase and no drugs can work on the G0 phase because the cell is dormant/sleeping and can’t be killed.
- S Phase is replicating phase
- Most drugs work on this phase
- G° Phase is non-replicating phase
- No drugs can work on this phase
Drug resistance
Just as we talked about bacterial resistance, the same thing happens with cancer cells. There is innate resistance where we know certain cancer chemotherapy drugs will not work against certain cancers. And then there’s acquired resistance where the therapy was working and then it stops working. And when that happens, we’re looking at acquired resistance on an individual level.
- Innate
- Acquired
Chemotherapy drugs kill by first order kinetics (half life)
First-order kinetics, when applied to the concept of cytotoxicity, means that the drug will kill a constant proportion of tumor cells (rather than a constant number). In other words, a specific dose kills a specific fraction of tumor cells regardless of the population. The term half-life is used because in first order kinetics a constant fraction of the drug in the body is eliminated during a unit of time. The rate of elimination of the drug is directly proportional to the amount of drug in the body (its plasma concentration). Another way to say it is that the body will process and eliminate “half” of the blood concentration of the drug every “half-life” period. So what is this constant proportion? Effective therapy kills 99.9% of all cancer cells. So we could put a person on a course of 3 chemotherapy drugs and kill 99.9% of the cancer cells. This sounds awfully good, doesn’t it? So why isn’t there curing going on all the time? A person that has a disseminated metastatic disease has somewhere in the vicinity of 1 trillion cancer cells (10^12). If one good course of chemotherapy kills off 99.9% of the 1 trillion tumor cells, what’s left? One billion cancer cells left (10^9). 🙁 Here’s the math:
- 100% – 99.9% = 0.1%.
- 0.1% = 0.001
- 0.001 x 1,000,000,000,000 (1 trillion) = 1,000,000,000 (1 billion)
Historically our problem had been that we had to wait several weeks before the next course of chemotherapy because we were also affecting the normal cells and the person was susceptible to infection and we had to wait for them to recover. In that course of time, since cancer cells grow fast, the tumor would be back up to 10^12 cells before the next course of therapy, which would again, kill 99.9% and they would go back down again. If we keep doing this and can get it down to 10^6 (1 million cells) and hopefully stimulate the persons immune system to try to fight off the remaining cancer cells, we could get them into remission. That’s the goal. If we could get them down to zero, then we are finally in remission. After 5 years of remission, they would be deemed to be cured. But in reality, that’s not actually true because there have been lots of horror stories of it coming back beyond 5 years later. Why are we only 0.1% away from killing off all the cancer cells? The reason we couldn’t kill all 100%, was because some of the cells were in that dormant G0 phase we talked about earlier! Today, we don’t have to wait 3 weeks for their white blood cell count to go up. We could give an injection of filgrastim which gets the immune system working again which we discussed in regards to anemia therapy.
Advantages of combination therapy
Chemotherapy is usually given as a combination of drugs to achieve that 99.9% kill rate. There is an unfortunate viewpoint we have to deal with when we think about chemotherapy and combination drugs: If a patient is going to be on three drugs, we can’t use three drugs that all have a major toxic effect on the bone marrow. So instead we choose drugs that have major toxicities to different parts of the body rather than all three having massive toxicity to one area (one that’s toxic to the bone marrow, one to the lungs, and one to the neurologic system). So you could imagine the hell people are going through.
Research has taught us the best way to schedule the regiment of cancer therapy. Like understanding what drugs we should give on exactly which days of the week for the best result. And we are also learning which drugs are the best combination that work against specific types of cancers.
Based on Body Surface Area
Chemotherapy drugs are dosed totally differently than anything else we’ve talked about previously. Rather than basing it on a persons weight or age, the dose is dependent on the body surface area. The average persons body surface area (BSA) is 1.7 meters squared but chemotherapy patients usually have lower body surface area. The dosage may read something like 10 mg/M²/day(10 milligrams per meters squared per day). There’s calculators that will figure it out for you and there’s nomograms that take into account the height and weight and tell you these things.
Recap
- Drugs kill by first order kinetics
- Effective therapy kills 99.9% of tumor cells
- Advantages of combination therapy and scheduling regimens
- Dose by surface area (mg/M²)
