Adverse effects of chemotherapeutic drugs | Pharmacology

Common adverse effects of chemotherapeutic drugs

Drug	Adverse effect
Vinca alkaloids	Peripheral neuropathy, bone marrow suppression, GI upset, alopecia
Taxanes	Peripheral neuropathy, edema, neutropenia, thrombocytopenia, hypersensitivity reactions; Thalidomide is teratogenic and causes limb defects like dysmelia
Methotrexate	Mucositis, skin and mucosal ulcers, GI toxicity, hepatotoxicity, pulmonary fibrosis; Prevent toxicity with prophylactic leucovorin/folinic acid
Mercaptopurine	Bone marrow suppression, cholestasis, jaundice
Irinotecan	diarrhea
Ifosfamide	Hemorrhagic cystitis
Cyclophosphamide	Hemorrhagic cystitis, bone marrow suppression, alopecia, GI upset, SIADH, pulmonary and cardiac toxicity
5 fluorouracil	GI upset, diarrhea, alopecia
Doxorubicin, daunorubicin	Cardiac toxicity, arrhythmias, cardiomyopathy, CCF; Liposomal formulations are less cardiotoxic; Dexrazoxane protects against cardiotoxicity. Dexrazoxane chelates iron, limiting the formation of free radical generating anthracycline-iron complexes, which prevents free radical mediated cardiotoxicity
Bleomycin	Pulmonary fibrosis, pneumonitis, hypersensitivity, hyperkeratosis, skin blisters
Cisplatin	Ototoxicity, neurotoxicity, peripheral neuropathy, vomiting, nephrotoxicity, myelosuppression
Cytarabine	Neurotoxicity, conjunctivitis, keratitis
Procarbazine	neurotoxicity, peripheral neuropathy, vomiting, myelosuppression, skin reactions and disulfiram-like reaction
Busulfan	Pulmonary fibrosis, adrenal insufficiency, skin pigmentation

Acrolein is a by-product of cyclophosphamide and ifosfamide. It is a bladder irritant and causes hemorrhagic cystitis. Treatment is by hydration and Mesna (mercaptoethanesulfonate).

Amifostine or ethyol is an antioxidant that is used to decrease nephrotoxicity caused by cisplatin and to reduce xerostomia resulting from radiotherapy to the head and neck.

Mechanism of resistance to chemotherapeutic drugs

Genomic instability and tumor heterogeneity
Cytokines, growth factors in the tumor microenvironment
Cancer stem cells escape drugs by overexpression of ATP binding cassette or ABC, drug transporters like ABCB1 and ABCG2 , drug efflux pumps, inhibition of apoptosis etc.
Drug inactivation by increased expression of the GST or glutathione S-transferase enzymes
Multidrug resistance by increased efflux of drug by ATP dependent transporters like P-glycoprotein, MRP1 and BCRP/ABCG2
Decreasing the absorption of drugs by decreasing the number of drug transporters
Inhibition of apoptosis by upregulation of anti-apoptotic genes Bcl2, AKT and down regulation of pro-apoptotic genes like Bax, Bclxl
Mutations in p53 gene
Altering drug metabolism by decreasing activation of prodrugs to drugs and increasing inactivation of drugs
Modification of drug targets like topoisomerases
Enhanced DNA repair
Gene amplification increases number of target genes like dihydrofolate reductase, oncogenes and oncoproteins
Epigenetic changes like DNA acetylation and methylation
Changes in micro RNA or miRNA regulating gene expression

Tumor lysis syndrome: It is a syndrome caused by the lysis of tumor cells, often after chemotherapy, leading to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. It manifests as renal failure, arrhythmias, seizures, tetany, carpopedal spasm, muscle twitchings and multiorgan failure. SIRS and cytokine release contribute to multiorgan failure. Uric acid and calcium phosphate stones may precipitate in the kidney. It is more often seen in leukemias and lymphomas. Prevention and treatment is with good hydration, diuretics like furosemide, if needed, to increase urine output, allopurinol and rasburicase (more effective) to decrease uric acid formation, treatment of hyperkalemia and dialysis, if necessary.