Combination Chemotherapy – Medicine’s Attempt to Beat Darwin
Evolutionary biologists have shown that DNA mutations lead to change. Change that increases survivorship will be expressed with increased frequency going forward. Change that weakens a species is bred to extinction.
In a healthy human cell line, DNA mutations are rare, occurring at the rate of two errors per 100,000,000 cell divisions. The extraordinary accuracy of replication explains why evolutionary change comes slowly under normal circumstances. Cancer cells behave differently. They are genetically unstable and are subject to frequent mutations. The rate of DNA errors in cancer cell lines is thought to be 50 to 750 times higher than the norm.
Cancer is a disease of abnormal and uncontrolled cell growth. Cells replicate by growing and dividing. Mutations can occur during DNA replication and cell division. As cancer progresses, the tumor makeup becomes a more heterogeneous mix; the result of mutations. The cells in a more mature tumor are less like the other cells than the cells in a new tumor. The new-found diversity makes treatment more difficult if resistant lines have developed in the changing mosaic of cells of the tumor.
Resistance in tumor cells is similar to that seen in bacteria. Penicillin was once a powerful antibiotic used to treat Staph infections (Staph aureus). Today it is rarely prescribed for skin infections. Bacterial mutations and the over use of penicillin have created the super-bug MRSA (methicillin-resistant Staph aureus). Evolution occurs quickly in bacteria as selective pressure kills the weak strain of Staph. What remains is the difficult to treat, multi-drug resistant Staph aureus known as MRSA.
Just as mutations in bacteria create infections that are resistant to antibiotics, mutations in cancer cell lines create tumors that are resistant to previously effective treatments. Relapses in cancer patients are thought to be the fruition of a small number of cancer cells that evade death by mutating into a resistant form. Initially, the patient may show great improvement until the new form of the cancer storms back.
Combination chemotherapy is medicine’s attempt to prevent mutation and resistance. By combining two or three chemotherapeutic agents the probability of killing the cancer rises. Cancer cells are attacked by multiple drugs that disrupt different stages of the cell reproduction cycle.
All cells go through five phases during the reproduction cycle. Many chemo drugs work only at a specific phase of the cycle while other drugs are not phase specific. It is logical to attack multiple phases of the cell replication cycle to prevent mutation and resistance from occurring.
Oncologists strategize when developing combinations. The first criterion is obvious; each agent must be effective against the cancer type. The different agents should attack the malignancy through a different mechanism of action. For example, one drug may disrupt DNA replication while a second drug interferes with protein synthesis. Attacking the malignant cells through different mechanisms lessens the chance of a mutated cell line evolving.
Combination drug selection must also consider toxicities. Good combinations avoid a heavy double insult to any one organ system. Each drug’s effect on bone marrow, liver and renal function must be considered. Drug toxicity can have an additive effect so oncologists want to avoid poisoning any part of the body too much.
A model of combination chemo therapy is illustrated in the treatment of lung cancer. One accepted treatment for small cell lung cancer is the use of cisplatin and etoposide along with external radiation. Cisplatin and etopiside make a good team as they have different mechanisms of action and divergent toxicities.
Cisplatin disrupts cell replication by cross-linking DNA strands. While effective killers of cancer cells, platinum drugs are notorious for renal toxicity. Renal function must be monitored and patients should be well hydrated before treatment.
Etoposide irreparably damages DNA and has a side effect profile typified by bone marrow suppression. Anemic etoposide patients have low red blood cell counts and neutropenic patients have low white blood cell counts due to bone marrow suppression. Neutropenic patients are at increased risk of infection as white blood cells are infection fighters. Anemic patients are often fatigued as red blood cells are required to carry oxygen throughout the body.
Cisplatin and etoposide have synergistic killing effects on cancer and unique side effect profiles making them a powerful combination in the treatment of lung cancer. Combination therapy is not just limited to drug combinations. As the treatment of lung cancer illustrates; radiation and surgery also play a major role in cancer treatment.
An idealistic goal for treating cancer is to remove all cancer cells from the body before they replicate and evolve into a resistant cell line. In this race against time combination chemotherapy is a fundamental tool in preventing the emergence of resistance. The history of mankind is written around attempts to control nature. Currently man and medicine are teamed in a fight against malignancy. When selected for premature death by cancer, the use of combination chemotherapeutic medicine greatly increases man’s odds for survival.