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)
Neoadjuvant chemotherapy
in cases when the local treatment (e.g. surgery) wouldn’t be totally curative or to increase the success rate of this aformentioned local treatment (purpose: decreasing the tumor size before surgery)
Adjuvant chemotherapy
administered after local treatment to inhibit the relapse of the tumor and to increase the life quality of the patient
