How Does Chemotherapy Work?
Obviously, chemotherapy works by killing cancer cells. In our current theory, it seldom, if ever, kills the last remaining cancer cells. Instead, it dramatically reduces the number of such cells, and the body’s immune system “mops-up” those few that remain. This is a paradox, since many chemotherapy agents weaken the immune system, thus compromising it’s ability to recognize and kill abnormal cells. Various agents kill cancer (and normal) cells in different ways, and it is instructive to get a better understanding of this process.
The study of how chemotherapy effects living cells is called molecular biology and this field has exploded with new information in the last 2 decades, as nuclear physics did in the early twentieth century under Einstein. To understand how chemotherapy effects both normal body tissues and cancers, we look at living organisms at their”cellular” level. All living things have as their basic unit the “cell” ; similar cells combine to form “tissues”, and tissues combine to form “organs” . This is analogous to the way in which atoms are the basic unit of elements, elements of molecules, and molecules of compounds. Simple creatures may have only a single cell (e.g. a bacterium or amoeba), while plants, animals and humans are composed of billions or trillions of cells. A spherical piece of flesh 1/2 inch across contains about a billion cells! In our bodies old or injured cells die, while new ones form – this constant process is crucial to continued life. We know that if we give enough radiation to any cell, it will die. To appreciate how chemotherapy works, however, we must look even deeper (smaller) than the cell, at it’s “subcellular” components.
Individual cells were first observed in the 17th century by Leiwenhook, who had invented the microscope. More powerful magnification showed a world of activity going on within cells, the process of “life” . Electron microscopes now show yet more.
The first thing noted was that every mammalian cell had a “membrane” around it, a darkly staining central spot called the “nucleus”, and between the outer membrane and the inside nucleus was “cytoplasm”fluid. Closer inspection showed the cytoplasm to actually be filled with apparent machinery, called”organelles” for small organs. The nucleus was made up of dark staining strands, called”chromosomes”. These chromosomes became especially visible when the cell divided, a process called”mitosis” . Furthermore, each chromosome was a slightly different shape, but they appeared to arrange into pairs at mitosis. Closer study of the chromosomes showed that there were 48 total in a humans, 23 which paired up as “autosomes” and 2 “sex chromosomes” . In females both “sex chromosomes” were called “X-chromosomes” (for their shape), while males had one “X-chromosome” and a smaller”Y-chromosome” . Staining and studying the chromosomes during mitosis was called a “karyotype”, and it was soon seen that various serious diseases corresponded to abnormal chromosome patterns . For example, in Down’s syndrome where severe mental retardation and abnormal features were present at birth, these children were shown to have three Chromosome #21′s (“trisomy 21″) instead of the normal two. In girls who had short stature, webbed neck, and were infertile, they were found to be missing one of their two sex chromosomes (“Turner’s syndrome”). Many such syndromes were found, but not every obviously inherited disease had clearly abnormal chromosomes.
It became obvious that chromosomes controlled heredity, and that one of each pair of chromosomes was inherited from each parent. Chromosomes themselves were found to be composed of thousands of much smaller elements called”genes”, short for “genetic materials”. Somehow, a”genetic code” existed that told the cell how to live, function, and even when to die. This code was “cracked” (to a point) in the 1950′s by Watson and Crick, who demonstrated the model for “Deoxyribose Nucleic Acids” (“DNA”) . These DNA molecules were shown to be twisted into a “double helix” which formed the genes. DNA itself was shown to be made up of a long “sugar” backbone (the “ribose”) and just four other molecules,(the “nucleic acids”). These four molecules (adenine, cytosine, guanine, and thiamine) were paired up on the two “strands” forming each double helix – adenine always paired to thiamine, while guanine always paired to cytosine. The amazing thing was, that the arrangement of these 4 molecules were different in every different gene, made up the genes, and so would determine every physical characteristic of every plant, animal and human! There were found to be about 3 billion “DNA base-pairs” in the human”genome”, different for everyone except identical twins. It was soon seen that damage to these ultramicroscopic (smaller than an ordinary microscope could see) base pairs were associated with every inherited disease known. For the cell to produce new products (“proteins”) the DNA double-helix “unzipped”, and a strand of “messenger RNA” was formed along one DNA strand. This RNA stand then separated from the parent DNA, and traveled outside the nucleus to the cytoplasm. In the cytoplasm exist protein manufacturing factories, called “ribosomes”, which get their message on what do do from the messenger RNA. Proteins and enzymes are then produced, which may utilized inside the cell, or sent outside of it as a “gene product” such as a hormone or antibody. Now we knew that if this process went awry, and DNA was damaged, cell products would be abnormal and disease could result.
One more important facet before describing chemotherapy effects is a deeper understanding of how cells divide. When the cells divided, the double helix of DNA base pairs “unzipped” and doubled itself by forming two new “complimentary” strands, using the two previous strands as a “template” . As mentioned, this process, called “mitosis” for regular body cells, is essential for life, but also for cancers to grow and spread. We know that we all start out in womb life from the contribution of a sperm from our father and an egg (“ovum”) from our mother. To form these “germinal cells” in our father’s testicles and mother’s ovaries (our parents “gonads”), a unique type of cell division occurred, called”meiosis” . For normal cell division, mitosis, the DNA duplicates (doubles), the divides in half, so we end up with 2 identical “daughter” cells(which can each go on to double their DNA and divide again). Each of these daughter cells still retains the contribution of DNA design from both parents, even if the individual is 100 years old. Thus, there is an identical type, and amount, of DNA in every body cell – each cell has within it the information on how to form a whole new body! Now if each parent gave us this type of cell, with a full amount of DNA, we would have enough information for two bodies – not one. Therefore, the “meiosis” process that occurs to make sperm and eggs cuts the amount of DNA in half, instead of ultimately keeping it the same like mitosis. Fascinatingly, the DNA is sliced in half differently for each sperm or egg produced, which explains why siblings look different. As will be seen, the testicles and ovaries are particularly sensitive to chemotherapy damage, and if they are “overdosed” then infertility (“sterility”) will result.
The sperm and egg combine upon the spongy inner lining of the uterus (“endometrium”), re-forming the normal amount of human DNA in this newly “fertilized egg”. From this point on, until the incipient child begins forming their own eggs or sperm at puberty, all cellular division is mitotic, not meiotic. Thus, the normal human compliment of DNA, one-half being from each parent, is restored in every cell division. The fertilized egg starts dividing, forming an”embryo” . At first, all of the cells are the same (“pleuripotential”), but then the genes within some of the cells activate and cause them to change (“differentiate”) from the other cells. Thus muscle, fat, heart, lung, bone, brain, skin etc. form, from these specialized cells. After 8 weeks, the embryo has a heartbeat and is recognizable as a tiny human, and is called a”fetus” .
From the fetal point onward, all the organs are formed, and the merely develop and grow larger.
In womb life, early childhood, and through puberty all of the body’s cells are “turned on” to divide and grow an adult human. The genes exert very exacting control over cellular division, to ensure that it does not run amok. Gradually, certain systems become fully grown, and cell division completely ceases. Other systems will regenerate new cells to replace those that have died as a result of old age or injury, while still others constantly generate new cells throughout life. For example, the brain cells (“neurons”) cease dividing by puberty, and will never divide again in a normal brain. The cells of the liver or skin are capable of dividing to replace injured ones, while the blood cells and intestinal lining are continuously being renewed. As long as tight control is maintained by the genes, everything grows in it’s proper time.
Each of the body’s cells has a specific “cell cycle” related to reproducing, and this cycle may change over time. The cell cycle, and thus division, is controlled by the genes. A cell may spend a prolonged period (or even the rest of it’s existence) in a quiescent period, where it is not reproducing (the “G1 phase”). If the genes trigger instructions for a cell division, the cell starts duplicating it’s DNA (the “S phase”). Once the DNA is doubled, it prepares to divide (the “G2 phase). Then the actual division takes place (the “M phase”) to produce two identical daughter cells. At certain points in the cell cycle, there are “checkpoints” to ensure that the DNA is intact, that is has doubled normally, and that the cell is indeed ready to divide. Each of these division checkpoints is controlled by genes, which should not let the division take place is something is wrong. Normally, this system works with incredible speed and harmony.
Now we have a background to understand what happens to make a cell turn cancerous . Something damages the genes that control cell division, resulting in a cell which divides out of control. That something may be a chemical (“carcinogen”), virus, radiation, or just a random”mutation” (change; deviation) that occurred during a previous division. Anything that damages the controlling genes in a cell can lead to cancer . The genes damaged may be the ones that “check” the cell at the division checkpoints, and so erroneously allow a damaged cell to divide. Alternatively, they may be the same genes that were normally turned on in the womb and childhood, but in adulthood they should be turned off (“oncogenes”) . Another scenario is the damaged genes are ones that normally suppress excessive division (“suppressor genes”) and now the cell divides without regulation. Whatever genes were damaged to cause cancer, it is ultimately a disease of the DNA, the molecules which form the genes. Chemotherapy can damage DNA or interfere with the protein products it produces, either killing a cell or causing it to become abnormal.
At the cellular level, then, chemotherapy either blocks something needed for the DNA to replicate (preventing cell division), or interferes with protein production by disturbing the RNA, ribosomes or their necessary “metabolites”. Since both division and protein production are essential to a cell’s functioning, derailing either effectively kills that cell. In cancer terms, a cell which can’t divide is as good as dead, for it can no longer add to the “tumor burden”. Interestingly, some cells produce proteins which act as local hormones and stimulate their own, or their neighbors division – these are called “autocrine” proteins. These are well described in brain cancer (“gliomas”). Being able to block these autocrine substances will naturally slow cancer replication. Of course, effectively blocking cancer cell division will also impair normal cell division, leading to side effects. This is less problematic when bacteria are treated with antibiotics, since the bacterial ribosomes are different than human (and animal) ribosomes. Therefore, bacterial reproduction can selectively be blocked by targeting those non-human ribosomes, leaving the human ones untouched. The problem in giving chemotherapy is that the DNA, RNA, Ribosomes and major Proteins within cancer cells are virtually the same as in normal cells! Of course, we said their are differences, for the DNA is damaged and abnormal RNA and proteins may be made. However, the differences are slight, often only at the gene level, and our current agents don’t distinguish normal cells from cancer cells at that level. The crude way we do distinguish normal cells from cancer cells is by the rate of cell division, which tends to be faster in cancer cells. Thus, depriving the cells of what they need to divide, or otherwise poisoning the division process, will tend to selectively weed out cancer cells first . Naturally, quickly dividing normal cells (i.e. blood cells, scalp hair follicles, gastrointestinal lining cells) will also succumb, explaining the classic side effects of chemotherapy. However, they can repair damage and heal better also.
The previous discussion also explains the paradox of why more aggressive cancers may actually be more easily cured than less aggressive (“indolent”) ones. Aggressive cancers (e.g. choriocarcinoma, lymphoblastic lymphoma, small cell lung cancer) tend to be quickly dividing and so rapidly killed off by chemotherapy. In contrast, more indolent cancers (e.g. low grade sarcomas, chronic lymphoma, hormone-responsive breast cancer) that are slower growing won’t be killed off much faster than slowly cycling normal cells (i.e. muscle, nerve, fat, bone) and so the chemotherapy will hit the normal cells just as hard. This causes the side effects of the required doses to kill off most all of the cancer cells too hard for the body to tolerate. Enough of the chemotherapy would decimate the cancer, but the patient would succumb also. Thus we are relegated to giving lower doses, which may (or may not) effectively kill enough cancer cells to make a noticeable(“clinical”) difference.
Interestingly, their is a range of sensitivities in the tumor cells (even a single patient in a single tumor). Some will be readily killed by the chemotherapy, but others will live. Even if 95% of the cancer cells are killed by the drug, the 5% remaining tend to be more resistant and require much more drug to kill them, probably more than the normal cells can tolerate. This is called the “Goldie-Coleman” hypothesis – as we are more successful in killing cancer cells, the remaining ones are the most impervious to our treatment . We need to kill the vastest majority right at the outset, since the resistant population can develop over time (much like insects grow resistant to pesticides). This is a major reason for using multiple drugs, and for using multiple therapies such as radiation and surgery together with chemotherapy, instead of waiting until the cancer grows back to try other therapies.
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