Topoisomerase inhibitors and chronic pain


Topoisomerase inhibitors emerged in the American medical landscape in 1971, thanks to the discovery by Dr. Jim Wang of the E. coli omega protein. Topoisomerase I, an enzyme identified by Dr. Wang, plays a crucial role in DNA unwrapping from supercoiling. Supercoiling involves tightly wrapping DNA for storage and protection, requiring unwrapping for reading, a process in which topoisomerase is indispensable.

Topoisomerase comprises two main types, aptly named types I and II. Type I (TOP1) aids in untwisting DNA for translation, whereas type II (TOP2) is pivotal in unlinking intertwined DNA molecules during replication and chromosomal segregation. In eukaryotic cells, topoisomerase II exists in two isoforms: II alpha and II beta. II alpha exhibits high expression in actively dividing cells, unraveling tangles and knots, while II beta is more associated with DNA repair and gene expression regulation, being implicated in tumors and neurodegenerative diseases when dysfunctional. Further elaboration on this point will follow.

Consider a person attempting to unravel a tightly tangled rope, encountering a knot that cannot be untied. The individual then cuts one strand of the rope, unties the knot, splices the rope back together, and continues working. This analogy illustrates how topoisomerase alleviates torsional strain on DNA molecules. Another analogy likens it to spinning a garden hose to relieve torsion when it becomes twisted. Omega protein controls gene expression necessary for genetic material transfer between bacterial cells by inhibiting topoisomerase I’s relaxation activity, keeping DNA wrapped up and unreadable.

All known life on Earth employs these enzymes. Once identified, it became evident that topoisomerase inhibitors could be valuable in treating infections and cancer by immobilizing the DNA in affected cells, rendering them unable to function or reproduce. Further discussion on this matter will follow, but in brief, TOP1 inhibitors such as camptothecin have shown high selectivity in cancer treatment. Derivatives like topotecan and irinotecan have gained approval for ovarian and colorectal cancer treatment.

Cancer treatments entail using medications known to be toxic when the risk to cancer cells outweighs that to normal cells, with the hope that cancer cells succumb before the patient does. However, other medical conditions can be equally severe. Drug-resistant infections like multidrug-resistant Staphylococcus aureus and Clostridium difficile pose significant challenges, becoming nearly untreatable in certain scenarios. Topoisomerase enzymes exhibit various variants across different life forms, allowing for targeting these variants to combat bacterial and parasitical infections. Topoisomerase IV and DNA gyrase, akin to alpha and beta, form a subtype of topoisomerase II unique to bacterial cells.

Targeting topoisomerase IV and DNA gyrase can disrupt bacterial function. Consequently, antibiotic medications were swiftly developed to target infections and, following safety testing, commenced global use. Some infections, like trypanosomiasis, have become nearly incurable without such medications. However, these medications, once widely used, were soon found to cause tendon and nerve damage, as well as heart arrhythmias, hypoglycemia, and gastrointestinal problems. Over time, they also became associated with chronic pain syndromes resembling fibromyalgia and chronic low back pain. As a result, it is now recommended to reserve these medications as a last resort, akin to chemotherapy.

This raises another issue. Presently, there are physicians who deny the existence of conditions like fibromyalgia, alleging that chronic pain and fatigue syndromes are fabricated by patients, consciously or unconsciously. This denial has significant implications, particularly for physicians treating pain, who should be well-informed about the challenges they face. Medically uninformed politicians and juries may buy into the notion that chronic pain syndromes aren’t genuine, urging patients to avoid medical professionals in favor of alternative healers.

Medical history is replete with instances where conditions not fully understood or curable were labeled as psychological problems. It wasn’t long ago when mothers were blamed for causing their sons’ schizophrenia or when stress alone was held responsible for all gastric ulcers. Notably, medical science initially refused to acknowledge that an infection, specifically Helicobacter pylori, could cause ulcers, a fact eventually proven by Dr. Barry Marshall of Australia through a daring self-experiment.

While it’s impossible to prove that none of those suffering from such syndromes have purely psychological causes, it’s evident that not all do. Fibromyalgia and similar syndromes have been associated with various factors, including genetic mutations, sleep disturbances, stress, immune and endocrine dysregulation, and exposure to biochemical agents, including topoisomerase inhibitors. A recent study published in the Korean Journal of Pain highlights the increasing evidence linking chronic pain to infections.

Infections can trigger inflammation and pain, with viral infections like herpes zoster and shingles causing excruciating neurogenic pain. Furthermore, the body’s immunological response to infection can lead to severe chronic pain, as seen in autoimmune conditions like rheumatoid arthritis and polymyalgia rheumatica. Notably, autoimmune conditions and chronic pain syndromes are more prevalent in women, prompting speculation about the interplay between immunological stressors, chronic pain, depression, and anxiety.

The analgesic effect of antibiotics appears to manifest in two ways: by reducing infectious burden and associated pro-inflammatory processes and by inhibiting signaling processes necessary for pain perception and maladaptive neuroplastic changes via off-target effects. Antibiotic treatment has shown promise in alleviating symptoms ranging from chronic low back pain to irritable bowel syndrome and chronic pelvic pain. Identified antimicrobial medications associated with pain improvement include cephalosporins, ribavirin, chloroquine derivatives, rapalogues like rapamycin, minocycline, dapsone, and pisidin-1.

In conclusion, the evidence suggesting that conditions like fibromyalgia can be induced by toxins and infections, and sometimes ameliorated by antimicrobials, underscores the need to take these conditions seriously. Physicians who dismiss these syndromes as psychological flaws exhibit extreme opinions contrary to evidence-based medical science. While individuals are entitled to personal opinions, advocating such views in legal settings as a standard of medical judgment is tantamount to medical malpractice. Physicians misleading juries with false statements regarding medical practices or practitioners should face consequences, including the loss of their medical licenses, as such actions undermine the integrity of both science and medicine.

L. Joseph Parker is a distinguished professional with a diverse and accomplished career spanning the fields of science, military service, and medical practice. He currently serves as the chief science officer and operations officer, Advanced Research Concepts LLC, a pioneering company dedicated to propelling humanity into the realms of space exploration. At Advanced Research Concepts LLC, Dr. Parker leads a team of experts committed to developing innovative solutions for the complex challenges of space travel, including space transportation, energy storage, radiation shielding, artificial gravity, and space-related medical issues. 

He can be reached on LinkedIn and YouTube.


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