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 - Monoclonal antibodies (Cont'd)

G.2. Bevacizumab (Avastin)

 

Angiogenesis is a normal physiological process related to the growth of new blood vessels from pre-existing vessels. Angiogenesis can be stimulated as a result of tumor growth. Therefore, modulating the abnormally high angiogenesis has become a strategy for anticancer research after Judah Folkman proposed the theory in 1971.

Bevacizumab is the first approved angiogenesis inhibitor in the U.S. It is a humanized monoclonal antibody that works by blocking vascular endothelial growth factor A (VEGF-A).

Bevacizumab, in combination with intravenous 5-FU–based chemotherapy, was approved by the FDA for first- or second-line treatment of patients with metastatic colorectal cancer in 2004. It was subsequently approved for lung cancer (2006) and breast cancer (2008).

Major side effects of bevacizumab includes hypertension, surgery wound healing problem, higher risk of bleeding, thrombocytopenia, gastrointestinal perforation, and nasal septum perforation. Other common side effects include lower white blood cell (WBC) count, vomiting, constipation, diarrhea, and hair loss.

© 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 - Monoclonal antibodies (Cont'd)

G.1. Cetuximab (Erbitux, ImClone)

Mutation by chemicals, virus, radiation etc. could cause the over-expression of EGFR. Resulting in uncontrolled cell division and is associated with a number of cancers such as lung cancer, colon cancer, and glioblastoma multiforme (the most common and aggressive brain tumor).

Cetuximab is a recombinant mouse/human (chimeric) monoclonal antibody that binds to the extracellular domain of the EGFR, thereby blocking the activation of EGFR to achieve its anticancer effect. It is used for the treatment of EGFR-expressing metastatic colon cancer after failure of irinotecan (Irinotecan, a semisynthetic analogue of the natural alkaloid camptothecin, is a drug used for the treatment of colon cancer) and oxaliplatin-based regimens. Cetuximab is used in treating colon cancer patients, either alone or in combination with chemotherapy.

Cetuximab is administered by infusion and may cause serious infusion reactions including rapid onset of airway obstruction, hypotension, shock, loss of consciousness, myocardial infarction, or cardiac arrest. Cetuximab may also cause electrolyte depletion for months after initiation of erbitux therapy.

© 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 - Monoclonal antibodies

G. Monoclonal antibodies

Monoclonal antibody (mAb) plays a critical role in recognizing foreign antigen and then either stimulating or inhibiting immunological or cellular responses. There are several ways that mAbs can be used for therapy.  For example, cetuximab is a monoclonal antibody that binds to the extracellular domain of EGFR thus achieving its anticancer effect by inactivating EGFR.

© 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 - Hormones

F. Hormones

Hormones are compounds internally secreted by a specific tissue/organ, transported by body fluids to another tissue/organ (receptor), and affect the function of the receptive tissue/organ. Most hormones exist naturally but some hormones can be synthesized.

For example, tamoxifen is a common hormone treatment for breast cancer.  Also, a phase II clinical study suggested that the concomitant administration of melatonin (a pineal hormone) and tamoxifen may induce tumor regressions in metastatic breast cancer patients refractory to tamoxifen alone.

Fig. 1.14   Structure of tamoxifen

Certain breast cancer cells require the activation of estrogen receptor to grow. Tamoxifen (Fig. 1.14) is first metabolized by human cytochrome P450 and its metabolites then compete with estrogen in binding to and inactivating estrogen receptor, thus hampering the growth of the breast cancer cells.

Tamoxifen was approved by the FDA in December 1977.  It is currently used for the treatment of both early and advanced estrogen receptor positive (ER+) breast cancer patients. In June 1990, tamoxifen was approved by the FDA for an additional use to help prevent the recurrence of breast cancer wherein the cancer cells have not spread to the lymph nodes under the arm. 

© 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 - Kinase Modulators (cont'd)

E.2. Afatinib (Gilotrif™, Giotrif®)

The commercial product of afatinib (Fig. 1.13) is an orally administered inhibitor of the ErbB family of tyrosine kinases. Afatinib also inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR). The inhibition is through the formation of a C-S covalent bond between afatinib and a cysteine in EGFR.

Fig. 1.13  Afatinib

Afatinib (Fig. 1.13) was first indicated for treating non-small cell lung cancer. In addition, it has been reported that afatinib may be useful to treat other cancers.

© 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 - Kinase Modulators (cont'd)

E.1. Imatinib mesylate (sold as Gleevec® by Novartis)

Fig. 1.12

Imatinib (Fig. 1.12) was first approved by the FDA in 2001 and sold as Gleevec^®. It works by specifically targeting, and turning off constitutively active tyrosine kinases (Bcr-abl) which help cancer cells grow and multiply. Bcr-abl kinase is a hybrid product of a chimeric Bcr-abl oncogene caused by translocation between chromosomes 9 and 22. The tyrosine kinases cause several cancers including Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) and gastrointestinal stromal tumor (GIST). Gleevac comes in tablet form. When given by oral administration, the active ingredient, imatinib, is rapidly absorbed.

Potential side effects of Gleevec include fluid retention, rash, nausea & vomiting, muscle cramps, and diarrhea. 

© 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 - Kinase Modulators

Chapter 2

Anticancer Drugs - E. Kinase Modulators

A protein kinase modifies a specific protein (substrate) by chemically adding a phosphate group (from ATP) to change the function/activity of the substrate that regulates the cellular pathways, especially signal transduction pathways. This process of adding a phosphate group to a substrate is referred to as phosphorylation. During the phosphorylation process, ATP loses a phosphate group and becomes ADP.

Phosphorylation is a very important reaction, which regulates a lot of biological processes. The phosphate groups are often added to tyrosine, threonine, or serine. As a result of the phosphorylation, many biological processes are regulated. Many diseases are due to the hyperactivity of protein kinases. Therefore, it makes sense to tackle these diseases by modulating the protein kinases.

More than 500 protein kinases have been identified in humans. For example, tyrosine kinase is an enzyme that helps attach a phosphate group onto a tyrosine residue in a protein; it is important in signal transduction and is implicated in the treatment of cancer.

Kinase modulators target a molecular abnormality by modulating the activity of certain kinase. Kinase modulators have been used in certain types of cancer. Examples of kinase modulators are shown below. 

© 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.2. Vinblastine

Fig. 1.10  Vinblastine

Vinblastine (Fig. 1.10) was first isolated from a Madagascar plant, periwinkle. Vinblastine has been used to treat Hodgkin’s lymphoma, lung cancer, and bladder cancer. It works as a mitotic inhibitor, similar to Paclitaxel through microtubule modulation by suppressing microtubule dynamics and the reduction microtubule mass.

© 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.