Cancer Metastasis

Cancer is a disorder by which abnormal cells proliferate uncontrollably and rapidly resulting in a tumour, this process is triggered by more than one factor which could be intrinsic (genetic), extrinsic (environmental) or both. The continuous growth of tumour cells is mediated by genomic and molecular mechanisms leading to the systemic spread of tumour cells to target the other parts of the body, this is called cancer metastasis. Metastasis is the primary cause of deaths from cancer, it accounts for more than 90% of cancer death.^1–3

Cancer chemotherapy

Cancer chemotherapy is a type of treatment indicated to kill rapid-growing cells (tumour cells). Regardless of the ongoing clinical studies that prove the importance of the new targeted therapeutics, such as cancer immunotherapy and personalised medicine, in terms of efficacy and safety, chemotherapy remains the most selective and frontline option to treat cancer, particularly during metastasis, advanced stages of cancer, and when other therapy options (surgery and radiotherapy) can not be opted, despite the potential side effects of chemotherapy. The survival rates for patients with metastatic cancer is still low due to the development of therapeutic resistance.^1,2

Types of the used chemotherapy in Metastatic cancer

Classification of chemotherapeutic agents

There are various chemotherapeutic agents that have been used in different types of cancers. These drugs are categorised based on their structure/source, efficacy against different types of cancers, mechanism of action, and biological target.²

Alkylating agents

Alkylating agents are one of the main groups of chemotherapy due to its chemical structure with electrophilic properties that can interact with cellular deoxyribose nucleic acid (DNA) resulting in covalent conjugates and DNA strand breakage. The mechanism of action of these drugs is by transferring alkyl group to the guanidine base (G) in DNA, then the incorrect base pairing takes place, impairing cell division. Thus, alkylating agents are the cornerstone of the chemotherapy against most of the cancer types. Examples on alkylating agents are

• Chlorambucil
• Altretamine
• Doxorubicin
• Platinum drugs (oxaliplatin, cisplatin, carboplatin)
• Etoposide
• Epirubicin
• Busulfan
• Mitoxantrone
• Thiotepa
• Cyclophosphamide

Side effects:

• Low blood count
• Nausea and vomiting
• Peripheral neuropathy
• Poor appetite
• Mouth sores
• Loss of fertility
• Diarrhoea

Antimetabolites 

This group of chemotherapy interferes with cellular metabolism. Antimetabolites exhibit a structure that resembles a cellular metabolite or enzyme-substrate. Thus, they act by producing certain substrates that hinders the normal substrate (unreduced dietary folates) to bind on the enzyme (dihydrofolate reductase) via the site of action, this prevents dihydrofolate reductase to produce tetrahydrofolate (folate insufficiency) which are utilised by cancer cells. Methotrexate is one of the main antimetabolites, it is an anti-inflammatory drug as well used in other inflammatory disorders such as severe psoriasis and rheumatoid arthritis. 

Pyrimidine antagonists (Pyrimidine-Derived Antimetabolites) and vinca alkaloids 

Pyrimidine antagonists are cytotoxic drugs that act by interfering with DNA synthesis. Cytarabine is one of the pyrimidine antagonists, it acts by impairing DNA and ribonucleic acid (RNA) synthesis as well through replacing the cytosine with itself. Cytarabine is also known as cytosine arabinoside, it is indicated to treat leukaemia or non-Hodgkin’s lymphoma. Other examples of pyrimidine-derived antimetabolites involved capecitabine, decitabine, gemcitabine, floxuridine, tegafur, raltitrexed, 5-fluorouracil (5-FU), and fluorouracil. These types of drugs are like pyrimidine or purine analogues (utilised for RNA and DNA synthesis), but with altered structure. Thus, during synthesis phase (S) of the cell cycle, they induce cellular death (apoptosis) through inhibiting the core enzymes (such as DNA polymerases) responsible for nucleic acid synthesis that forms the RNA and DNA.

Side effects:

• Diarrhoea
• Elevated liver enzymes
• Low white blood cells count
• Low red blood cells count
• Vomiting
• Rash and itching
• Fatigue
• Hand and foot syndrome
• Headache
• Mouth sores
• Flu-like
• Hair thinning
• Weight loss
• Dehydration

Vinca alkaloids are primarily cell division inhibitors extracted from the Vinca genus. They interfere with cell mitosis through inhibiting a protein known as tubulin. The most common drugs of this group are vinblastine and vincristine, they possess different degrees of antitumor activity. These drugs are used against rhabdomyosarcoma, miscellaneous myeloma, Hodgkin's and non-Hodgkin's lymphoma, acute leukaemia, thyroid cancer, Wilms tumour, Ewing’s sarcoma, different blood-related diseases, and brain tumours. 

Side effects

• Fatigue
• Low blood counts
• Injection site reactions
• Alopecia
• Neurotoxicity
• Hair loss
• Myelosuppression

Other antineoplastic drugs

This group is one of the promising cancer chemotherapy. This group of drugs exhibits different mechanistic pathways that cause cell death (apoptosis).

Side effects:

• Nausea and vomiting
• Headache
• Fatigue
• Cough
• Abdominal pain
• Rapid heartbeat (tachycardia)
• Shortness of breath
• Sore throat
• Elevated blood glucose level
• Blurred vision
• Face swelling
• Numbness
• Itching
• Sleep difficulty
• Joint pain

Paclitaxel (Taxol)

It is a drug containing taxane ring extracted from the bark of the Western yew tree (Taxus brevifolia) which exhibits cytotoxic activity against cancerous cells. Paclitaxel interferes with the function of tubulin and microtubules that induce cell death. It acts by stabilising microtubules assembly through promoting the assembly of tubulin into microtubules, this results in maintained microtubules without undergoing breakdown, unlike aforementioned alkaloids. Paclitaxil demonstrated antagonist activity against bosom carcinomas and metastatic ovarian. Additionally, it has also confirmed efficacy against small cell lung cancer, advanced stage cancer of neck and head disorder, prostate cancer, and esophageal adenocarcinoma. Docetaxel is another potent anticancer drug under the same category of paclitaxel, but it is more potent compared to paclitaxel in terms of efficacy against ovarian and bosom cancers.

These drugs recorded many side effects, particularly after long exposure, which primarily includes neuropathy, neutropenia, arrhythmia, and cardiovascular concerns. 

Etoposide

Etoposide is a semi-synthetic cytotoxic drug which is derived from a glycoside of a plant known as podophyllotoxin. Etoposide cytotoxic activity is caused by the breakdown of the DNA strands through interfering with the DNA topoisomerase-II function and altering the G2 phase of cell cycle. Moreover, DNA topoisomerase-II is a core enzyme for the cell cycle during proliferation promoting DNA synthesis, for this reason tumour cells rely on this enzyme to grow faster. Thus, Etoposide impairs this enzyme activity inducing cell death (apoptosis). Etoposide maintains potent activity against different types of malignancies including glioblastoma multiforme, lung disease, non-lymphocytic leukaemia, lymphoma, Kaposis’s sarcoma, Ewing’s sarcoma, and testicular disorder.

Camptothecin 

Camptothecin is derived from plant origins known as bark of the tree Camptothica acuminata. This drug acts through inhibiting topoisomerase enzyme which results in tumour cell death. After that, more potent drugs were synthesised and derived from camptothecin such as topotecan, one of the most common drugs of camptothecin derivatives. Topotecan has a notable activity against lung and ovarian cancers, it works by inhibiting topoisomerase-I, which results in alteration of the DNA replication and growth arrest. Another important derivative called irinotecan has reported efficacy against aggressive cancers of the cervix, ovary, lungs, and colon. Additionally, irinotecan has a cytotoxic activity against late-stage colorectal cancer.

Actinomycin D

It was originally derived from Streptomyces sp and indicated as an antibiotic, but later it has demonstrated an antitumour activity to treat Wilms tumour, Ewing’s sarcoma, trophoblastic neoplasm, rhabdomyosarcoma, ovarian and testicular cancer, etc. It acts by binding to DNA strands forming a highly stable drug-DNA complex. 

Mitomycin C

It is an alkylating agent derived from Streptomyces caespitosus. It impairs continuous cell cycle through the mechanism of cross-linking between DNA bases that results in disrupted DNA replication. This drug has an efficacy against cervical, pancreatic, colorectal, esophageal, and breast cancers, in addition to non-small cell lung carcinoma.

Bleomycin

Another streptomyces derivative inhibits DNA replication by hindering thymidine to be incorporated into DNA strands, thus inhibiting DNA synthesis. Besides, there is another mechanism of action by which it chelates metal ions to form superoxide radicals interfering with DNA synthesis. It is effective against squamous carcinoma cells of the skin, testicular cancers, ovarian cancers, and Hodgkin’s lymphoma.

Conclusion and future directions

Chemotherapy is the frontline and cornerstone of cancer treatment. There is an emerging era in drug discovery that studies new designs of new derivatives of the old anticancer drugs that aim to possess high efficacy and the lowest toxicity by following strategies of combination therapies. This can be achieved in the future through incorporating chemotherapeutic agents with personalised medicine, targeted drug delivery, and immunotherapy. Despite the ongoing studies on chemotherapy, further research is required to optimise the combinational therapy approaches.

Summary

• Cancer is a disorder by which abnormal cells grow rapidly without control
• Chemotherapy remains the frontline and most opted option to treat cancer
• There are several chemotherapeutic agents to treat different types of cancers. These drugs are classified based on their structure/source, efficacy against different types of cancers, mechanism of action, and biological target
• The main chemotherapy agents that are used in metastatic cancer are:
  • alkylating agents
  • antimetabolites
  • pyrimidine-derived antimetabolites
  • other antineoplastic drugs
  • paclitaxel
  • etoposide
  • camptothecin
  • actinomycin D
  • mitomycin C
  • bleomycin
• The common side effects of chemotherapy are: hair loss, malaise, nausea, vomiting, low blood count, elevated liver enzymes, numbness, hand and leg syndrome, flu like symptoms, sore throat, skin problems, itching and rash, sleep difficulty, loss of appetite, blurred vision, headaches, and joint pain
• There is ongoing research focusing on the development of more effective and less toxic derivatives of existing drugs and incorporating them with personalised medicine, immunotherapy, and targeted drug delivery