Antineoplastic Drugs & Toxicities

Cancer is an abnormal mass of tissue due to the abnormal proliferation of cells. Also called Neoplasia/Carcinoma. Normal cells grow, differentiate, mature and divide/have a regulated balance between cell birth and death. (Balance b\w proto-oncogene and tumor suppressor genes).

Anti cancer drugs were discovered in 1940[Nitrogen Mustard ] was the first drug related to sulphur containing mustard gases. Others were discovered b/w 1950-1970

Cancer accounts for 20-25 % of deaths in clinical practices

Aim of Rx is total tumor cell kill/maximum cytoreduction. Attempts to cure or palliate cancer employ three principal methods;

Surgical intervention

Radiotherapy

Chemotherapy

Differing from the operation & radiotherapy that emphasize on the treatment of local tissues, the chemotherapy is concerned with that of the whole body.

Tumour cells can be classified as;

1. Proliferating cells

2. Non-proliferating cells

The ratio of proliferating cells in the whole tumour tissue is called growth fraction (GF). The faster the tumour cells proliferate, the bigger the growth factor is & the higher is the sensitivity of tumour to a drug. Generally, in the early stage, the growth of a tumour is bigger & the effect of a drug on the tumour is better. 

Causes of Cancer 

Physical Agents: UVRays, ionizing radiation[Ca skin, lungs breast, osteosarcoma]

Biologic Agents:

Bacterial Agents: Peptic ulcers and chronic gastritis if left untreated, causes gastric carcinoma.

Fungal Agents: Aspergillus flavus.

Viral Agent: Ca cervix, Burkit’s lymphoma, Hepatic carcinoma.

Chemical Agents

Genetic Factors

Dietary Habits

Hormones and Drugs 

Classification of Anti-Neoplastic drugs

According to chemical structure & sources of drugs.

Alkylating agents, antimetabolite, antibiotics, plant extracts, and hormones.

According to biochemistry mechanism of anticancer action.

Block nucleic acid biosynthesis

Direct influences the structure & function of DNA.

Interfere transcription & block RNA synthesis

Interfere protein synthesis & function

Influence hormone homeostasis

According to cycle or phase specificity of the drug.

Cell cycle nonspecific agents (CCNSA) & cell cycle specific agents (CCSA).

General Rules of Chemotherapy

Supportive Therapy:

 Antiemetics

Antibiotics

Prophylaxis of urate nephropathy

Enteral and parenteral nutrition

Analgesia

Psychological support 

Principles of Combination Therapies

In order to enhance curative effect, to decrease the toxicity & to reduce the drug resistance, combination therapies are often used in the treatment.

Advantages of drug combination;

They provide maximal cell kill within the range of tolerated toxicity.

They are effective against a broader range of cell cycle phases.

They may slow or prevent the development of resistance.

Select drugs according to their phase specific characteristics.

The aim of this rule is to urge more G0 Phase cells to enter the proliferating cycle so as to increase the amount to tumour cells killed by drugs.

Toxicity of the Anticancer Drugs:

Acute toxicity

Common toxicity

Myelosuppression

Gastrointestinal disturbance

Alopecia

Specific toxicity

?Cardiac toxicity: Doxorubicin

?Liver toxicity: , Dactinomycin

?Bladder toxicity

?Neurotoxicity: VCR

?Hypersensitivity: Taxol

Chronic toxicity

Infertility, teratogenesis, carcinogenesis

Countering Toxicities

Intermittent therapy

Folinic acid rescue

Systemic mesna (Sodium-2-mercaptocthane sulfonate) administration & irrigation by acetylcysteine –  detoxify toxic metabolites.

Ondansetron

Hyperurecaemia: Uricosuric agents like allopurinol

Platelet & granulocyte transfusion

Granulocyte colony stimulating factors (GM-CSF/G-CSF) – recovery of granulocytopenia.

Conclusion

Awareness / Education

Avoid risk factors

Eat healthy diet

Avoid obesity

Be physically active

Participate in screening programs

References 

Elsevier https:// evolve.elsevier.com/Haveles/pharmacology

Pharmacological basics of therapeutics (Goodman Gillmans)

Guidelines from Royal College of Obstetricians & Gynecologists (UK)