Anti Cancer Drugs: Mode of action and Adverse effects

When it comes to anti-cancer drugs, there are several major classes including alkylating agents, antimetabolites, natural products and more. There are also a number of drugs that do not fall within the given classes but still show anti-cancer activity. 

Read this blog post to learn everything you need to know about anti-cancer drugs for your Pharmacology paper and elevate your NEET PG preparation. 

What is Cancer?

• Cancer is an abnormal proliferation of cells. Cancer cells undergo uncontrolled proliferation or division, while normal cells have controlled division.

What are the Modalities of Treatment for Cancer

• Surgery
• Radiotherapy
• Chemotherapy (Anti-cancer drugs)
  • Anti-cancer drugs cannot differentiate between normal and cancerous cells and target the division of both normal and cancerous cells.

Common Adverse Effects of Anti-Cancer Drugs

• Since hair follicles are also dividing, reversible alopecia is seen with anti-cancer drugs. The mucosa of the mouth regenerates daily; after administering anti-cancer drugs, the mucosa is not able to regenerate, and the mucosa becomes inflamed. This is called Mucositis. This is prevented by Palifermin (Keratinocyte growth factor).
• Due to bone marrow suppression, immunity comes down, and the patient is prone to opportunistic infections.
• The management of decreased WBC is done with
  • GM CSF (Granulocyte-Monocyte Colony Stimulating Factor) analogue.
  • G-GCF (Granulocyte-Colony Stimulating Factor)- Filgrastin, Pegfilgrastim (longer acting) and Lenograstin.
• Decreased RBC production results in anemia. Treated by stimulating Erythropoietin.
  • Darbepoetin and Epoetin are used to treat anemia due to anti-cancer drugs.
• Thrombocytopenia is treated with Oprelvekin.

Bone Marrow-Sparing Anti-Cancer Drugs

• Some anticancer drugs do not suppress the bone marrow and only kill the cancer cells.
• These drugs are
  • Vincristine
  • Bleomycin
  • L-asparaginase

GIT

• In GIT, the cells are also killed, and serotonin is released, resulting in nausea and vomiting.
• Chemotherapy-induced nausea and vomiting (CINV), if occurs within 24 hours of starting chemotherapy, is considered early CINV.
• Drug of choice is 5HT3 antagonist
  • Ondansetron
  • Palonosetron
• Late CINV happens within 1 to 5 days of starting chemotherapy.
• Neurokinin 1 receptor antagonists are the drug of choice. 
  • Aprepitant
  • Fosaprepitant
  • Netupitant
  • Rolapitant
• To prevent CINV, the best combination is a 5HT3 blocker, neurokinin 1 receptor antagonist, and dexamethasone given prior to chemotherapy. The steroids decrease the inflammatory process.
• The drug of choice for cancer-induced diarrhea is loperamide.

Gonads

• In males, stops the multiplication of the cells and leads to oligospermia and in the females, there is decrease in Oogenesis ultimately leading to infertility.
• Anticancer drugs are contraindicated in pregnancy as they are teratogenic.

Radioprotector

• Amifostine is used to decrease radio sensitization during radiotherapy.

Tumor Lysis Syndrome

• In leukemia or lymphoma, plenty of WBCs are killed, and there is the release of purine.
• The patient experiences hyperuricemia, known as tumor lysis syndrome.
• The treatment is started with allopurinol; in resistant cases, the overall drug of choice is Rasburicase. This drug immediately converts uric acid to allantoin, which is water-soluble. 
• Allopurinol only blocks the synthesis; it cannot bring down the levels of uric acid.

Hypercalcemia

• In hypercalcemia of malignancy, the levels of calcium shoot up suddenly.
• Calcitonin, Furosemide is a loop diuretic, and zoledronate is a bisphosphonate, used to manage hypercalcemia of malignancy.

How Do Anticancer Drugs work?

• The types of Anti-cancer drugs:
  • Cytotoxic drugs
  • Hormonal agents
  • Targeted therapy

Cytotoxic Drugs (Non-Targeted Drugs)

• The two types are
  • Cell cycle non-specific
  • Cell cycle specific 
• G0 phase do not multiply like in the brain and heart.
• GS is the normal phase: Etoposide
• S is the synthesis phase: Anti-metabolites (Purine antagonist, Pyrimidine antagonist, Folate antagonist and Hydroxyurea)
• M is the mitotic phase: Bleomycin, DNA topoisomerase 1 & 2 inhibitors.
• In cancer cells, these checkpoints are not there, so they keep on replicating.

Cell Cycle-Specific Drugs

• The drugs that interfere with DNA synthesis are known as anti-metabolites.
• Methotrexate also acts on the S phase.
• Drugs that act on the G2 to M phase include:
  • Anticancer antibiotic bleomycin.
  • DNA topoisomerase I and II inhibitors.
• Mitosis means cell division. During cell division, microtubules contract and pull the DNA to the opposite end, and the cell divides.
• Microtubule Inhibiting agents (VEEET mnemonic). These drugs act on the M phase and interfere with microtubules, and damage them.
  • V - Vinca alkaloids: these are obtained from a plant.
  • E - Estramustine: It is used in prostate cancer.
  • E - Epothilones: it is used in breast cancer.
  • E - Eribulin
  • T - Taxanes

Cell Cycle Nonspecific Drugs

DNA Alkylating Agents

• These drugs enter the cells and produce highly reactive carbonium ions.
• These ions bind at the N⁷ guanine residue.
• They cause cross-pairing and mismatch in the DNA.
• The damaged DNA can proliferate and can lead to secondary cancers. This leads to cell death or the damaged DNA can proliferate and lead to secondary cancer.
• Drug Resistance in Cancer Cells:
  • The cancer cells have a p-glycoprotein efflux pump that resists the drugs, and hence in most cancers a combination of drugs is used to avoid drug resistance.

Mechlorethamine

• Mechlorethamine was used to treat Hodgkin’s lymphoma but it caused skin blisters.
• MOPP regimen is not used nowadays. (Mechlorethamine, Oncovin, Prednisolone and Procarbazine)
• The new regimen for Hodgkin's lymphoma is ABVD
  • Adriamycin, Bleomycin, Vinblastine and Dacarbazine
  • Adriamycin is also known as doxorubicin or hydroxydaunorubicin.

Melphalan

• It is used to treat Multiple myeloma.

Busulfan

• It is used to treat Chronic myeloid leukemia
• Adverse effect: Pulmonary fibrosis and Sinusoidal obstruction syndrome.

Chlorambucil

• It is oral drug of choice for Chronic lymphocytic leukemia 

Cyclophosphamide

• It is a product that needs to be converted to the active form by cytochrome 2B6 which gives rise to 4-hydroxy cyclophosphamide.
• This is converted to Aldophosphamide which in turn gives rise to Phosphoramide mustard and Acrolein.
• The phosphoramide mustard component produces an anti-cancer effect.
• Acrolein is another component that causes hemorrhagic cystitis, resulting in pain in the supra-pubic region.
  • MESNA (mercapto-ethanesulphonate) binds to acrolein and prevents this problem.
• Cyclophosphamide is one of the highly emetogenic drugs.

Uses of Cyclophosphamide 

• It is used in autoimmune disorders and is the drug of choice in Wegener’s granulomatosis and steroid-dependent nephrotic syndrome.
• It is also used in the treatment of rheumatoid arthritis but is not the first-line drug.
• Cyclophosphamide is mainly used as an anticancer drug, in the treatment of non-Hodgkin's lymphoma.
• The regimen used for non-Hodgkin’s lymphoma is R CHOP.
  • R - Rituximab (CD20 blocker)
  • C - Cyclophosphamide.
  • H - Hydroxydaunorubicin
  • O - Oncovin (Vincristine)
  • P - Prednisolone
• Also used in breast cancer. The regimen is called CMF
  • C - Cyclophosphamide.
  • M - Methotrexate
  • F - 5 fluorouracil

Ifosfamide

• It is a less emetogenic drug.
• It causes more hemorrhagic cystitis and is highly neurotoxic.
• Ifosfamide produces metabolite chloroacetaldehyde which is why it is highly neurotoxic.

Nitrosoureas

• The drugs are
  • Carmustine
  • Lomustine
  • Semustine
• These are highly lipid soluble so they easily cross the blood-brain barrier and are hence used in the treatment of brain tumors.
• Being lipid soluble, these can easily cross the bone marrow and result in sustained neutropenia.

Streptozocin

• It is used in experiments to induce diabetes in rats (as it damages the pancreas) and in certain cancers.

Procarbazine

• Procarbazine is a MAO inhibitor. 
• It should not be consumed with alcohol, as it causes a disulfiram like reaction.
• Procarbazine is also known to produce secondary leukemia.
• Procarbazine and dacarbazine are used in the treatment of Hodgkin’s and non-Hodgkin's lymphoma.

Temozolomide 

• It is used in the treatment of brain tumor, glioblastoma multiforme.

And that is everything you need to know about Anti Cancer Drugs for your Pharmacology paper. For more informative and interesting blog posts to upgrade your NEET PG Pharmacology preparation, download the PrepLadder App and keep following our blog.