B.29 Flashcards
Drugs in cancer treatment I (antimetabolite)
Antifolates: Methotrexate, Pemetrexed
Fluoropyrimidines: 5-Fluorouracil, Capecitabine
Deoxycitidine analogs: Cytarabine
Purine antagonists: 6-Mercaptopurine
Classification of antitumor agents
- Cytotoxic antitumor agents
- Cytostatic antitumor agents
- Cytotoxic antitumor agents
- Direct effect on cell proliferation
- Toxic (because there’s no basic difference between the division of normal and malignant cells)
- Relative selectivity (because the malignant cell division happens faster than the normal, but so the fast dividing normal cells are more affected→myelosuppression, GI symptoms, mucositis, alopecia)
- Cytostatic antitumor agents
- Effect by modifying the regulatory systems of cell proliferation
Complications of cytotoxic agents
- Nausea, vomiting
- Diarrhea
- Myelosuppression
- Neutropenia
- Mucositis
- Alopecia
- Pain
- Nausea, vomiting
- Types: acute (within 24h), delayed (after 24h)
- Epidemiology: 30-60% of patients
- e.g.: Cisplatin
- Treatment: Prophylaxis: dexamethasone, NK1-R antagonists; In refractory cases: various groups → olanzapine, D2-R antagonists etc
- Diarrhea
- Casue e.g.: Irinotecan, 5-FU
- interesting fact, in the case of vinca alkaloids, constipation shows because of the effects of the vinca alkaloids on cholinergic neurons
- Treatment: rehydration, constipants (loperamide)
- Myelosuppression
- all patients must be monitored brfore every treatment cycle
- treatment: modifying the protocol, tranfusion, CSFs
- Neutropenia
- Attention to neutropenic fever, rapid antimicrobial therapy necessary
- Antimicrobial prophylaxis: co-trimoxazol (Pneumocystis Jirovecii), Fluconazole (candidiasis)
- Mucositis
- Ulcerative and inflammatory lesions on the GI tract
- Treatment: adequate nutrition and hydration, pain treatment (2% viscous lidocaine, 0.5% doxepin, 0.2% morphine - Americal protocol)
- Alopecia
- Present in 65% of the patients
- reversible, but rarely permanent
- Treatment: preventive: combing, dying and ironing should be avoided, cooling with ice; Post chemotherapy: bimatoprost solution to the edge of the eyelid in case of palpebral alopecia, minoxidil locally
- Pain
- Depending on acute or chronic pain: Acute- start with interventional treatment→strong opioids→ weak opioids→ non-opioid analgestics; Chronic pain- non-opioid analgestics→weak opioids→ strong opioids→ interventional therapy
Drugs in cancer treatment - classification
- Antimetabolites
- Alkylating agents
- Topoisomerase inhibitors
- Mitotic spindle inhibitors
- Antimetabolites
- Antifolates: Methotrexate, Pemetrexed
- Fluoropyrimidines: 5-fluorouracil, Capecitabine
- Deoxycitidine analogues: Cytarabine, Gemcitabine
- Purine antagonists: 6-mercaptopurine, Fludarabine, Cladribine
5-Fluorouracil
MOA: specific for S-phase.
5-FU is uptaken by the cell →it is metabolized to FdUTP (deoxynucleotide analog) and FUTP (nucleotide analog)→FdUTP inhibits thymidylate synthase (no dTMP synthesis)→ inhibits DNA/RNA synthesis→ cell apoptosis. It also inhibits Thymidylate synthase and no dTMP is produced→also leading to apoptosis;
Kinetics: i.v. adm., good distribution in bowel mucosa, BM, liver and brain, metabolized mainly in the liver (CYP2C9), T1/2 rises with dose, it is broken down also by DPD (→the partial or full deficiency of DPD by AR inheritance may lead to severe toxicity);
IND: metastatic colorectal cc - anal and rectal cc combined with radiotherapy (combined with leucovorin), progressive metastatic breast cc, Progressive stomach cc, progressive pancreatic cc, progressive metastatic squamous cell head & neck cc, esophageal cc, cervical cc, renal cell cc;
SEs:
-Cardiac☠ (ischemia/infarct, HF, arrhythmias, angina),
-CNS☠ (disorientation, ataxia, visual disturbances, cerebellar syndrome, hyperammonemic encephalopathia),
-Gastrointestinal☠ (mucositis, stomatitis, esophagopharyngitis, ulcers, diarrhea),
-Myelosuppression⇊ (neutropenia, thrombocytopenia, anemia),
Hand-foot syndrome, Mutagenic, carcinogenic, teratogenic, possible infertility;
Extra: combined with leucovorine it has increased toxicity/cytotoxic effect
Capecitabine
MOA: specific for S-phase.
Prodrug of 5-FU (→metabolized to 5-FU→ 5-FU is taken by the cell→ metabolized to FdUTP (inhibitsThymidylate synthase) and FUTP→ encorporated in DNA/RNA→ apoptosis.
it also inhibits Thymidylate synthase→no dTMP is produced→apoptosis);
Kinetics: p.o (food has effect on the velocity and quality of abs.), Prodrug of 5-FU, excreted with urine (higher plasma levels in renal failure);
IND: progressive/metastatic colorectal cc, progressive/metastatic breast cc, progressive stomch cc;
SEs: see 5-FU, SJS, hyperbilirubinemia
Cytarabine
MOA: Specific for S-phase. enters the cell →metabolized to ara-CTP (nucleotide analog)→ ara-CTP blocks DNA polymerase-α,β→no DNA synthesis or repair + incorporation of non-functional nucleotide;
Kinetics: i.v adm., metabolized rapidly by liver and kidney;
IND: ONLY hematological malignancies → AML/ALL, CML, Meningeal leukemia or other meningeal neoplasms, non-Hodgkin’s lymphoma;
SEs: myelosuppression, mucositis, vomiting, nausea, neurotoxicity (in high doses)
6-Mercaptopurine
MOA: metabolized to 6-thioinosinic acid → inhibits various enzymes of the de-novo purine synthesis. The triphosphate form incorporates into DNA and RNA; Kinetics: Metabolized in the liver by xanthine-oxidase (in case of coadministration with allopurinol the dose must be reduced);
IND: childhood ALL, immunosuppression (transplantations, SLE, IBDs, Vasculitis diseases);
SEs: myelosuppression, GI, Hepatotoxicity, secondary tumors
Methotrexate
MOA: Antimetabolite.
MTX inhibits DHF-reductase→ no tetrahydrofolate synthesis→ no folate synthesis. MTX also inhibits Thymidilate synthase→ no dTMP synthesis →no DNA synthesis.
Intracellular MTX-polyglutamate metabolite accumulates in malignant cells and inhibits AICAR-transformylase →less immunosuppressive effects of AICAR;
Kinetics: adm. p.o, i.v., intrathecally, s.c.;
IND: Oncological diseases (breast, head&neck, urinary bladder, lung cc, osteosarcoma, leukemias, trophoblastic neoplasia - ectopic pregnancy), autoimmune diseases (RA, Psoriasis);
SEs: liver damage (enzyme level↑, liver fibrosis), mucositis, stomatitis, diarrhea, nephrotoxicity, fibrotic pneumonitis, myelotocicity, megaloblastic anemia, teratogenic;
Contra-IND: pregnancy, breastfeeding;
Reduce SEs: coadminister with leucovorine- a glucarpeptidase, can also be administered in case of overdose
Pemetrexed
MOA: Antimetabolite.
Inhibits folate-dependent enzymes-Thymidylate-synthase and DHF-reductase → no de-novo synthesis of thymidine and purine nucleotides;
Kinetics: adm. i.v., intrathecally, s.c.;
IND: oncological diseases- malignant pleural mesothelioma, NSCLC;
SEs: hand-foot syndrome, mucositis, diarrhea, fatigue, rash, myelotoxicity (neutropenia, thrombocytopenia, anemia), teratogenic
General formation of oncological diseases
Tumors form when the cellular mechanisms of normal (healthy) cell survival, proliferation and/or differentiation are disturbed, and the cells start proliferating
Leucovorin
MOA: Active folate;
IND: to reduce MTX or pyrimethamine toxicity, folate deficiency, MeOH intoxication, with 5-FU to increase cytotoxic effect (→colorectal cc, pancreatic cc)
ways to treat tumors
- Non-pharmacological ways:
- Surgery
- Radiotherapy (irradiation) - Pharmacotherapeutic ways:
- Primary chemotherapy
- Neoadjuvant chemotherapy
- Adjuvant chemotherapy
Primary chemotherapy
for patients with progressive and/or metastatic tumors, who cannot be treated with other ways because of various reasons (e.g. inoperability)
