Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy (Cont'd)

Additional information about the side effects of radiotherapy

Because a human body is a delicate and complicated biological system, and the inter-communication among different organs are even more complex, some side effects are inter-connected and may not be clearly separated from one another. Let’s use some examples for further illustration.

Cancer patients treated by high dose radiation onto specific organ may suffer organ damages in addition to other side effects (hair loss, diarrhea, etc.). Let’s look at the radiotherapy on liver cancer as a specific example. Patients with liver cancer, when treated by ionizing radiation, may suffer from liver damage and/or liver function reduction.

There are several reasons why organ damages occur after radiation therapy. The obvious reason is that liver cells damaged by DNA will result in the damage of liver tissue through mechanisms such as programmed cell death (apoptosis). The other important reason is that certain cytokines, such as TNF-a, in liver and blood are often markedly induced by radiation therapy. As described before, abnormally elevated levels of TNF-a will kill the surrounding cells (no matter cancer cells or normal cells), and will cause certain liver damage. 

Our experimental results showed that radiation in mouse liver induced liver damage (reflected by elevated serum levels of both aspartate transaminase (AST) and alanine transaminase (ALT), and the liver damage is in correlation with increased levels for serum TNF-a induced by irradiation. Pre-treatment of mice with a small-molecule TNF-a modulator UTL-5d (Fig. 2.2) effectively reduced TNF-a secretion and resulted in marked reduction of ALT/AST levels. This implies that TNF-a may play an important role in damaging the liver and UTL-5d compound may be a potential agent for radioprotection.

                                                                    Fig. 2.2   Structure of UTL-5d

    In order to reduce the side effects induced by radiotherapy, there are several general strategies being employed as described in the next chapter. 

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy (Cont'd)

1.       Damage to the DNA of normal cells 

 The potential adverse effects of radiotherapy to the DNA of normal cells may result in tissue/organ damage and potentially secondary cancer. This is mainly due to (1) the direct exposure of normal cells to radiation, and (2) the indirect effect from the free radicals generated by radiation, which might result in the modification of certain genes generally referred to mutation. As a result, there is a possibility that certain cancer might be induced in the future, also known as secondary cancer, especially if high radiation dose is used often. 

In recent years, significant technical improvements have been made to greatly reduce this type of potential side effect. Examples of the newer radiotherapy technologies are described in the following chapter.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy

Although radiotherapy is a major and often effective modality in treating cancer patients, it can inflict serious damage on healthy tissues/organs. Because radiotherapy utilizes high energy radiation to kill cancer cells, injury to normal organ is almost inevitable. For example, the acute side effects of radiotherapy can occur on any surrounding normal tissues be it skin, brain or lung.

     Fortunately, many of the side effects caused by radiotherapy are reversible, but some may not become apparent until months or even years later, such as secondary tumor formation. Fortunately, modern technologies in radiotherapy can significantly reduce the radiation exposure of normal tissues and reduce the side effects thereof.

In general, the side effects of radiotherapy can be summarized in the following four categories:

          1. Damage to the DNA of normal cells
2. Damage to cell renewal
3. Activation of immunologic responses
4.  Other side effects of radiotherapy

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 1 - Introduction

PART II

Chapter 1

Introduction (cont'd)

Radiotherapy has been used for both curative and adjuvant cancer treatment for many years. Adjuvant therapy refers to auxiliary/additional treatment for cancer; adjuvant radiotherapy is usually given after surgery or in conjunction with chemotherapy when a potential risk of relapse remains. Radiotherapy can also be given before surgery to reduce the mass of tumor to be removed.

Roughly speaking, 60% of all cancer patients receive radiotherapy, thus, radiotherapy might not be necessary for all cancer cases. For example, according to a scientific report in the New England Journal of Medicine, it was indicated that children with the most common form of leukemia can safely forego radiation therapy if they are treated with chemotherapy regimens tailored to their individual needs. The conclusion was based on a clinical trial involving 498 patients with acute lymphoblastic leukemia.  Nearly 94 percent of the patients were still alive 5 years after treatment, a result that compares favorably with other treatment studies.

An overly simplified schematic representation of how radiation works is shown in Fig. 2.1. Basically, radiation therapy works by damaging the DNA of cancer cells and hampering these cells from replicating. The damage to cancer cells is caused by radiation, which directly or indirectly breaks up the DNA chain. The indirect damage comes from free radicals including hydroxyl radical (HO^·), superoxide  (O₂^-), hydrogen peroxide (H₂O₂), peroxyl (ROO^·) and alkoxyl (RO^·) radicals, collectively called reactive oxygen species (ROS).  

Fig. 2.1   Schematic representation of how radiation works

© Jiajiu Shaw, 2020

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 2 - Other Types of Anticancer Drugs

H. Other Types of Anticancer Drugs

Generally speaking, drugs in categories A to D affect DNA synthesis and/or cell division; they can also attack fast growing normal cells, including bone marrow cells, hair follicle cells, and crypt cells as mentioned before. The drugs in categories E to G including kinase modulators, hormone treatment, and mAbs can modulate tumor cell behavior without directly attacking DNA in those cells.

Other than those in these A-G categories, a number of newer approaches have been developed or under development. For example, making antibody-drug conjugates (ADCs) is one of the newer approaches. In an ADC, a potent anticancer drug is covalently linked to an antibody (the whole mAb or a fragment of an antibody) corresponding to specific antigen differentially overexpressed in cancer cells. With this design, the conjugate is able to discriminate between cancer cells (target of the antibody) and normal cells; once the ADC hooks up with the cancer cell, the potent anticancer drugs is released and attack the cancer cell. The end result is that anticancer effect may be increased and the side effects may be reduced.

© Jiajiu Shaw, 2019

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.

Chemotherapy and Its Side Effects: Chapter 2 - Antibiotics

Chapter 2

Anticancer Drugs - D. Antibiotics

There are a number of antibiotics being used as anticancer drugs. Examples of antitumor antibiotics include doxorubicin, dactinomycin, epirubicin, and bleomycin. DNA binding agents can have a number of outcomes which result in cell death. They usually are planer in structure and multi-ringed to allow them to non-covalently bind to the bases in DNA (and RNA). Compounds like actinomycin D turn off RNA syntheses once they intercalate with the DNA. Compounds, like bleomycin, create free radicals after intercalating with DNA strands.

In this section, we will focus on a class of anticancer drugs, anthracyclines. Anthracyclines are derived from Streptomyces bacteria. They are used to treat a number of cancers, including breast, ovarian, and lung cancer as well as leukemia. Anthracyclines are known to form intercalation with DNA to achieve anticancer effect although the complete mechanism is somewhat complex (intercalation is a reversible inclusion between two different molecules or groups). Anthracyclines have played a very important role in chemotherapy and have been used in many different types of cancers.

Although anthracyclines are effective against more cancers than most other classes of anticancer drug, anthracyclines do have several adverse effects including cardiotoxicity. A specific example of anthracyclines, Doxorubicin, is described below.

Doxorubicin (trade names: Adriamycin PFS, Adriamycin RDF, or Rubex)

Doxorubicin (Figure 1.11) is closely related to another anthracycline occurred naturally, daunorubicin. Just like all anthracyclines, doxorubicin intercalates with DNA and causes structural distortion of DNA. As a result, replication of DNA is inhibited and cancer cells eventually die. However, this intercalation with DNA can also happen to normal cells and causes significant side effects.

Fig. 1.11  Doxorubicin (left) and daunorubicin (right)

Doxorubicin is commonly used in the treatment of a wide range of cancers, including breast, ovarian, and lung cancer as well as leukemia. Doxorubicin is administered intravenously and its main side effects include cardiomyopathy, myelosuppression, and secondary malignancies.

© Jiajiu Shaw, 2019

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 2 - Mitotic ihibitors (Tubule inhibitors)(Cont'd)

C.1. Paclitaxel (Sold as Taxol®)

Paclitaxel (Fig. 1.9) was isolated from the bark of the Pacific yew, Taxus brevifolia, by Monroe Wall and Mansukh Wani in 1967.  It was co-developed by NCI and Bristol-Myers Squibb. The drug product was approved as Taxol® by the FDA in 1992. Since its approval, Taxol has been used to treat patients with ovarian, lung, and breast cancer for a number of years. 

Fig. 1.9   Structure of paclitaxel

Paclitaxel works by hyper-stabilizing microtubules, major components of the dynamic cellular skeleton (cytoskeleton), to interfere with the normal breakdown of microtubules in the M phase of cell cycle (mitosis). In eukaryotic cells (cells with a nucleus), the cell cycle can be divided in two brief periods: interphase and the mitosis. During the interphase (I), the cell grows, accumulating nutrients and duplicates its DNA. During the mitosis phase (M), the cell splits itself into two distinct daughter cells. As a result of paclitaxel treatment, which hyper-stabilizes microtubules and hampers the mitosis, cancer cells are not able to replicate.

Similar to all other anticancer drugs, paclitaxel has a number of side effects. Serious side effects include unusual bleeding, skin rash, change in bowel habits, fever, chills, cough, difficulty swallowing, dizziness, shortness of breath, as well as severe exhaustion.

© Jiajiu Shaw, 2019

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 2 - Antimetabolites (Cont'd)

B.2. Fluorouracil (5-Fluorouracil or 5-FU)

Fluorouracil (Fig. 1.7) is sold under different trade names such as Adrucil and Efudex.  It is classified as an antimetabolite and has been used for treating cancer for many years. Due to its similarity to thymine, 5-FU interrupts the synthesis of thymidine, one of the building blocks of DNA. As a result, DNA replication is interrupted and the growth of cancer cells is hampered.

Fig. 1.7   5-FU (left), thymine, and thymidine (right)

Fluorouracil has been used mainly in treating colon cancer and has been used in combination with other drugs, including leucovorin, carboplatin, and paclitaxel.  It has also been used in other solid tumors including pancreatic cancer and breast cancer. Side effects of fluorouracil include myelosuppression, dermatitis, and mucositis.

© Jiajiu Shaw, 2018

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 2 - Antimetabolites (Cont'd)

B.1. Methotrexate (also referred to as amethopterin)

Methotrexate has been used for treating cancer and autoimmune diseases for many years. Although it has been off-patent for many years, it is still very highly prescribed.

Methotrexate is an antimetabolite that interferes with the use of folic acid. As shown in Figure 1.6, the structures of methotrexate and folic acid are strikingly similar. Because folic acid is essential for the synthesis and repair of DNA, especially during cell growth and division, it is logical that methotrexate interferes with the growth of cancer cells.

Methotrexate is cytotoxic and has a wide range of potential side effects including myelosuppression and mucositis. Methotrexate is also highly teratogenic and should not be taken by women during pregnancy or expected to be pregnant. It is generally true that no chemotherapy is given for pregnant women and, for women of child-bearing age, precaution must be taken.

Fig. 1.6   Structures of methotrexate (left) and folic acid (right)

Sometimes, folic acid is used to reduce the side effects of methotrexate. However, folic acid could act as an antidote to methotrexate, therefore, it is better to use folic acid on the off days during methotrexate treatment.

© Jiajiu Shaw, 2018

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 2 - Antimetabolites

Chapter 2

Anticancer Drugs - B. Antimetabolites

An antimetabolite is a drug that interferes with normal cell metabolism by inhibiting certain metabolite pathways and stopping cell growth or cell division. The molecular structure of an antimetabolite is usually similar to the metabolite that they interfere with. They usually induce cell death during the S phase of the cell cycle.

For example, folic acid is an important component in the synthesis and repair of DNA and RNA. An analog of folic acid, methotrexate, has a structure that is almost identical to that of folic acid but acts very differently; methotrexate inhibits cell division to achieve its anticancer effect.

© Jiajiu Shaw, 2018

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 2 - Alkylating Agents (Cont'd)

A.4. Cisplatin and other platinum drugs

Cisplatin, cis-dichlorodiammine platinum(II) (Fig. 1.4), is the grandparent of all platinum drugs. It is a widely prescribed anticancer drug with therapeutic activity against various solid tumors, but also with substantial side effects. The anticancer activity of cisplatin was discovered by Dr. Barnett Rosenberg of Michigan State University in 1965 [2]. In 1978, the first formulated pharmaceutical product of cisplatin, Platinol, was approved by the FDA and sold by Byistol-Myer Squibb.

As an alkylating agent, the platinum ion of cisplatin forms coordination bonds mostly with guanine on DNA. This crosslinking causes the interference of DNA replication, thus, inhibits the replication of cancer cells.

Fig. 1.4   Cisplatin, carboplatin, and oxaliplatin

Since the discovery of cisplatin’s anticancer activity, thousands of cisplatin analogues have been made and/or studied. Two of the notable platinum drugs successfully developed by Bristol-Myers Squibb are carboplatin and oxaliplatin (Fig. 1.4); both were approved by the FDA for treating a variety of cancers.

In the last thirty years or so, the impact of platinum drugs on cancer treatment has been tremendous and has benefited many cancer patients. However, because platinum drugs are often associated with significant side effects, scientists are still working on finding better platinum compounds with fewer/less side effects. Currently, there are a number of new platinum drugs under investigation or development, including some of the platinum compounds synthesized by one of the co-authors, Dr. Jiajiu Shaw. A couple of these new platinum compounds are shown in Fig. 1.5. The dinuclear platinum compound is the first to show a coordination bond between the amide oxygen and platinum(II).

Fig. 1.5  Examples of a 3-Nitrogen Pt compound (left) and a dinuclear Pt compound (right)

© Jiajiu Shaw, 2018

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Chemotherapy and Its Side Effects: Chapter 2 - Alkylating Agents

Chapter 2

Anticancer Drugs - A. Alkylating Agents

A classical alkylating agent works by attaching an alkyl group or a small molecule to hinder/stop the replication of DNA in cancer cells. Classic alkylating agents include nitrogen mustard, and cyclophosphamide. Platinum drugs are a different type of alkylating agent. Instead of directly attaching an alkyl group onto DNA, a platinum drug forms coordination bonds with DNA and hampers the replication of DNA. Some examples of alkylating agents are described below.

© Jiajiu Shaw, 2018

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

What Can One Do to Reduce the Chances of Getting Cancer - Follow Nature's Rules (13)

Follow the Old Chinese Philosophy, Zhong-Yong

Zhong-Yong is an old and respectable Chinese life philosophy; I think it is worthwhile to understand it in order to lower the risks of cancer.  “Zhong” means to be moderate and not to be extreme.  Whether dealing with people or issues, do it in a proper and correct way.  “Yong” means to be normal and to be just like ordinary people.  One does not have to be the strongest or richest.  However, one does not need to be the weakest or the poorest.  In my interpretation, the essence of Zhong-Yong in real life means to be moderate in treating your own body and to act as an ordinary person.

I believe the philosophy of Zhong-Yong can be applied to improve one’s health.  Whether it’s one’s eating or exercising habit, be moderate and do it within sensible limits.  As to one’s activity and behavior, be normal according to nature’s rules. 

I also believe Zhong-Yong is a very good principle of reducing the risk of cancer.  Think about how normal cells become cancer cells?  One important factor is that when normal cells are subject to abnormal/unnatural conditions, they are forced to be under a variety of stress and, as a result, there is a higher chance for the DNA to be damaged.  If the damages are not repaired by the body’s automatic repairing system, the DNA could be mutated and might result in cancer.  In short, even normal cells want to be under the appropriate condition (Zhong) and remain normal (Yong) per natural’s rules.  Why can’t we learn from the cells?

© Jiajiu Shaw, 2017

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book I wrote, "IS CANCER IN US", published recently.

Natural Products for Cancer Prevention/Management (6)

Eggplant

Eggplant is loaded with vitamins and minerals, but its additional health benefits may be surprising to most people.  Eggplant contains an interesting antioxidant, chlorogenic acid, which has a number of biological activities including blood-pressure lowering, antiviral, and antibacterial effects.  In addition, it also protects DNA from mutations and may have anti-cancer properties.

In addition, there is another antioxidant found in the peels of eggplant, nasunin.  Studies indicate that nasunin is anti-angiogenic, meaning that it could cuts off the new blood supply that cancer cells need in order to multiply. 

© Jiajiu Shaw, 2016

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book I am writing, "IS CANCER IN US", to be published in about two months.