Drugs

Chemotherapy literally means treatment of a disease by drugs. But the term has become a synonym with chemotherapy of tumors. Tumor chemotherapy is one of the basic pillars of cancer treatment, others being surgery and radiotherapy form the basic pillars of cancer treatment. Tumor chemotherapy drugs are also called anti-neoplastic drugs.

Chemotherapy works by killing the cancer cells. Cancer cells or cancerous cells are fast-growing cells which lack the normal regulation and check placed by the body.

Usually, chemotherapy drugs work by damaging the RNA or DNA of the tumor cells.

Chemotherapy can be used alone or used in conjunction with surgery and radiotherapy. Following protocols have been defined.

Types of Chemotherapy

Adjuvant chemotherapy

Surgery is done to remove the tumor and chemotherapy given to destroy microscopic cells that may be present after surgical removal. These if left uncontrolled can lead to recurrence.

Neoadjuvant chemotherapy

In this, the chemotherapy is given prior to the surgical procedure. This preoperative chemotherapy is given to attempt to shrink the tumor size and may change its staging, and demand less extensive surgery.

Induction chemotherapy

Chemotherapy is given to induce a remission.  This term is commonly used in the treatment of acute leukemias.

Consolidation chemotherapy

This is the chemotherapy given once a remission is achieved and the goal of the treatment is to sustain a remission.  It is also called intensification therapy This term is commonly used in the treatment of acute leukemias.

Maintenance chemotherapy

This is a low dose chemotherapy given in lower doses to assist in prolonging a remission in certain types of leukemias.

Palliative chemotherapy

As the name suggests, this chemotherapy is given to reduce the symptoms and does not aim to treat cancer. This is chosen when the malignancy is advanced and cannot be treated.

Drugs Used in Chemotherapy

Chemotherapy is designed to kill tumor cells but the drugs cannot differentiate between a cancer cell and a tumor cells.

Some drugs that kill cancer cells only when they are dividing. These are called cell-cycle specific.

Chemotherapy drugs that kill cancer cells when they are at rest are called cell-cycle non-specific.

Chemotherapy is most effective at killing cells that are rapidly dividing.

Following are the main groups of drugs used.

Alkylating Agents

Alkylating agents are most active in the resting phase of the cell.  These types of drugs are cell-cycle non-specific.  There are several types of alkylating agents used in chemotherapy treatments:

• Mustard gas derivatives
  • Mechlorethamine
  • Cyclophosphamide
  • Chlorambucil
  • Melphalan
  • Ifosfamide.
• Ethylenimines
  • Thiotepa
  • Hexamethylmelamine.
• Alkyl sulfonates
  • Busulfan.
• Hydrazines and Triazines
  • Altretamine
  • Procarbazine
  • Dacarbazine
  • Temozolomide.
• Nitrosoureas
  • can cross the blood-brain barrier
  • Carmustine
  • Lomustine
  • Streptozocin.
• Metal Salts
  • Carboplatin
  • Cisplatin
  • Oxaliplatin.

Plant Alkaloids

Plant alkaloids are chemotherapy treatments derived made from certain types of plants.

The plant alkaloids are cell-cycle specific.  They attack the cells during various phases of division.

• Vinca alkaloids
  • Vincristine
  • Vinblastine
  • Vinorelbine.
• Taxanes
  • Paclitaxel
  • Docetaxel.
• Podophyllotoxins
  • Etoposide
  • Tenisopide.
• Camptothecin analogs
  • Irinotecan
  • Topotecan.

Antitumor Antibiotics

Antitumor antibiotics are drugs made from the fungus Streptomyces.  These drugs are considered cell-cycle specific.  There are several types-

• Anthracyclines
  • Doxorubicin
  • Daunorubicin
  • Epirubicin
  • Mitoxantrone
  • Idarubicin.
• Chromomycins
  • Dactinomycin
  • Plicamycin.
• Miscellaneous
  • Mitomycin
  • Bleomycin.

Antimetabolites

Antimetabolites are agents with a similar structure to substances within the cell and get incorporated into the cellular metabolism. But they do not provide the required metabolites and the cancer cells fail to divide.  Antimetabolites are cell-cycle specific. various drugs in this group are

• Folic acid antagonist
  • Methotrexate.
• Pyrimidine antagonist
  •  5-Fluorouracil
  • Foxuridine
  • Cytarabine
  • Capecitabine
  • Gemcitabine.
• Purine antagonist
  • 6-Mercaptopurine
  • 6-Thioguanine.
• Adenosine deaminase inhibitor
  • Cladribine
  • Fludarabine
  • Nelarabine
  • Pentostatin.

Topoisomerase Inhibitors

Topoisomerase enzymes control the structure of DNA necessary for replication Topoisomerase inhibitors interfere with the action of topoisomerase  I and II.

• Topoisomerase I inhibitors
  • Ironotecan,
  • Topotecan
• Topoisomerase II inhibitors
  • Amsacrine
  • Etoposide
  • Teniposide

Miscellaneous

• Ribonucleotide reductase inhibitor
  • Hydroxyurea.
• Adrenocortical steroid inhibitor
  • Mitotane
• Enzymes
  • Asparaginase
  • Pegaspargase.
• Antimicrotubule agent
  • Estramustine
• Retinoids
  • Bexarotene
  • Isotretinoin
  • Tretinoin

Novel agents for the targeted therapy, immunotherapy, and hormone therapy are discussed later.

Routes Used for Chemotherapy

Chemotherapy can be given orally as well as parenterally. The common routes used are

• Oral
• Subcutaneous Injection
• Intra-Muscular Injections
• Intravenous
• Intraventricular/Intrathecal
  • Direct delivery to the cerebrospinal fluid
• Intraperitoneal
  • Directly into the abdominal cavity.
• Intra-arterial
  • Into the artery that is supplying the blood to the tumor.
• Intravesicular
  • Via the urinary catheter into the bladder
• Intrapleural
  • Directly into the pleural cavity
• Implants
  • Used in brain tumors, specifically glioblastoma multiforme
  • Placed and left in the cavity after surgical removal of a brain tumor
  • Delivered directly to the site of the brain tumor.
• Topical
  • For skin cancers
  • Applied over the lesion
  • Very limited role

Response to Chemotherapy

The response is gauged by many factors. These are

• Reduction of tumor size on examination/imaging
• Improvement in blood indices
• Tumor marker levels

Response to cancer treatment can be complete or partial.

Complete Response

• All of cancer/tumor disappears
• No evidence of disease left
• Tumor marker, if there is one, falls within the normal range.

Partial response

• Cancer has shrunk to some extent but the disease remains
• The tumor marker may have fallen but evidence of disease remains.

Additional Cancer Therapies

Targeted Therapy

Targeted therapy is more targeted on tumor cells by acting on features unique to cancer cells. This would kill less normal/healthy cells and lead to fewer side effects.

But it should be kept in mind that targeted therapies are not a replacement for traditional therapies.  More research is needed in this field.

Following targeted therapies are known

• Signal Transduction Inhibitors
  • Imatinib Mesylate – Protein-tyrosine kinase inhibitor
  • Gefitinib – epidermal growth factor receptor tyrosine kinase inhibitor
  • Cetuximab – Epidermal growth factor receptor
  • Lapatinib – Epidermal growth factor receptor and human epidermal receptor type 2 tyrosine kinase inhibitor.
• Biologic Response Modifier Agent –  Denileukin Diftitox
• Proteasome inhibitor –  Bortezomib

Monoclonal Antibodies

These can be used in cancers where antigens and the respective antibodies have been identified.  The following agents are available –

• Alemtuzumab
• Gemtuzumab ozogamicin
• Rituximab
• Trastuzumab
• Ibritumomab Tioxetan

Angiogenesis Inhibitors

This stops the process of angiogenesis or the formation of new blood vessels. The tumors need blood vessels in order to grow and spread.  Stopping these vessels by angiogenesis inhibitors would lead to starvation of tumor cells. At least in theory.

These agents are being studies and the benefits and risks would be determined after rigorous work only.

Immunotherapy

Immunotherapy is a form of biologic response modification. It is a treatment that is able to trigger the immune system to indirectly affect tumors.

The agents include cytokines such as interferons and interleukins. Larger doses of these agents are given by injection or infusion so as to stimulate the immune cells more effectively.

Colony-stimulating factors are substances that stimulate the production of blood cells and promote their ability to function

Fever, chills, nausea, and appetite loss, rashes or swelling are common side effects.

Tumor Vaccines

This is still under research. The idea is to develop vaccines that may encourage the patient’s immune system to recognize cancer cells.

Hormone Therapy

These agents act by stopping the production of a certain hormone, blocking hormone receptors, or substituting chemically similar but unusable molecules.

Various agents used are

Adrenal Steroid Inhibitors

• Interferes with the hormones produced by the adrenal gland and affects the production of estrogen, androgens, glucocorticoids, and mineralocorticoids.   Interfere with the stimulation of hormone influenced tumors
• Aminoglutethimide, mitotane

Androgens

• oppose the activity of estrogen, thereby slowing the growth of estrogen-dependent tumor

• fluoxymesterone, testosterone, testolactone

Antiandrogens

• Block the effects of testosterone.
• Cancer of the prostate depends on the male hormone testosterone for its growth.
• bicalutamide, flutamide, nilutamide

Antiestrogens

• Antiestrogens bind to estrogen receptor site on cancer cells
• blocking estrogen from going into the cancer cell.
• Tamoxifen, toremifene

Aromatase Inhibitors

• Aromatase inhibitors block the enzyme aromatase
• Aromatase convert androgens
• Effective in the estrogen dependent tumor.
• anastrozole, exemestane, letrozole

Estrogens

• Bind androgen receptor sites
• Decreases the influence of androgens (testosterone and androsterone) on prostate cancer.

• DES(diethylstilbestrol), estradiol (estrace), premarin

Luteinizing Hormone-Releasing Hormone (LHRH) Agonists

• Signal brain to  stop luteinizing hormone production
• LH stimulates the release of testosterone in men and the ovaries in women
• Goserelin acetate, leuprolide acetate, triptorelin pamoate

Progestational Agent

• Progestational agents have anti-estrogen effects
• Medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol, progestins

Selective Estrogen Receptor Modulators (SERMs)

• Drugs having estrogen-like action in some organs and as an anti-estrogen in others.  For example, Raloxifene acts like estrogen to prevent bone loss but it has the potential to block some estrogen effects such as those that lead to breast cancer and uterine cancer.
• Raloxifene

Chemoprotective Agents

Chemoprotective agents are drugs that are used with certain types of chemotherapy to protect the body from side effects of drugs or minimize the side effects of the chemotherapy. Examples are

• Dexrazoxane – Decrease in cardiac events
• Mesna – decrease bladder irritation (hemorrhagic cystitis)

Resistance to Chemotherapy

Chemotherapy resistance occurs when cancers that have been responding to a therapy suddenly begin to grow.

Causes of resistance are

• Mutation in surviving cells
• Gene amplification causing overproduction of protein rendering the drug ineffective.
• The drug is pumped out of cell fast using p-glycoprotein.
• Repair of DNA injury
• Inactivation of drug

The development of drug resistance is one reason that drugs are often given in combination

Side Effects of Chemotherapy

Chemotherapy attacks cells that are dividing and the parts of the body where normal cells divide frequently are likely to be affected by chemotherapy.  These include mouth, intestines, skin, hair, bone marrow are commonly affected by chemotherapy.

In regards to the effects, every person does not experience adverse effects. Different people may experience different side effects.

Nausea, vomiting, diarrhea, glossitis, loss of hair, bone marrow suppression and weakness are the common side effects.

Almost all side effects are temporary.