Antifolátové cytostatikum na liečbu malígneho mezoteliómu pleury a nemalobunkového karcinómu pľúc Pemetrexed je antifolátové cytostatikum (antagonista kysliny listovej, ktorý inhibuje tymidylátsyntetázu (TS), dihydrofolát reduktázu (DHFR) a glycínamidribonukleotidformyltransferázu (GARFT) a blokuje tak na folátoch závislú biosyntézu tymidínu a purínových nukleotidov. Pemetrexed sa pomocou transportných systémov dostáva do bunky a v bunke sa enzýmom folylpolylglutamátsyntetázou mení na polyglutamáty. Biologický polčas pemetrexedu je 3,5 hodiny a 70 - 90 % podanej dávky sa vylučuje v nezmenenej forme obličkami. Podáva sa v dávke 500 mg/m2 vo forme intravenóznej infúzie. Na zníženie toxicity musia pacienti liečení pemetrexedom dostávať tiež vitamínovú suplementáciu (kyselina listová a vitamín B12). Pemetrexed je indikovaný u pacientov s neresekovateľným malígnym mezoteliómom pleury a to v kombinácií s cisplatinou u pacientov bez predchádzajúcej chemoterapie, v monoterapii na liečbu v druhej línii s lokálne pokročilým alebo metastatickým nemalobunkovým karcinómom pľúc okrem prevažne skvamóznej bunkovej histológie, v prvej linií v kombinácii s cisplatinou na liečbu pacientov s neoperovateľným, lokálne pokročilým, alebo metastatickým nemalobunkovým karcinómom pľúc okrem prevažne skvamóznej bunkovej histológie, ktorí sa predtým nepodrobili chemoterapeutickej liečbe tohto stavu.
Kľúčové slová: pemetrexed - antifolát - malígny mezotelióm pleury - nemalobunkový karcinóm pľúc

PEMETREXED - PYRIMIDINE ANTIFOLATE FOR THE TREATMENT OF PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA AND NONSMALL CELL LUNG CANCER

Pemetrexed, a pyrriol(2,3d) pyrimidine antifolate, is unique among the folate antagonists in that it is a powerful inhibitor of not only thymidylate synthase (TS) but also dihydrofolate reductase (DHFR) and the purine synthetic enzyme, glycinamide ribonucleotide formyltransferase (GARFT). Like methotrexate (MTX), pemetrexed enters cells primarily via the reduced folate carrier (RFC), a low affinity high capacity active transporter. Once inside the cell, pemetrexed is an excellent substrate for the ubiquitous enzyme folylpolyglutamate synthetase (FPGS) and is converted to tri and pentaglutamates. This conversion results in even more potent inhibition of TS and GARFT. The main target of pemetrexed is considered to be TS, although in a colorectal cancer cell line, resistant to specific TS inhibitor raltitrexed, due to TS amplification, pemetrexed is still active, indicating that inhibition of DHFR and of GARFT plays a role in its activity. At high pemetrexed concentrations, hypoxanthine in addition to thymidine is necessary to rescue tumor cell lines from cytotoxicity. These observations provide further evidence that inhibition of purine synthesis is an important mechanism of action in pemetrexed's cytotoxicity. Low serum homocysteine levels are sensitive indicators of folate and vitamin B12 deficiency and are associated with pemetrexed induced toxicity, that is, thrombocytopenia, neutropenia, diarrhea, and mucositis. In patients who undergo treatment with pemetrexed, supplementation with folic acid and vitamin B12 avoided severe druginduced toxicities with no apparent reduction in the cytotoxicity of the drug. In addition, patients tolerate higher levels of drug with vitamin supplementation. Pemetrexed is indicated in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. Pemetrexed is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous nonsmall cell lung cancer, for the maintenance treatment of patients with locally advanced or metastatic nonsquamous nonsmall cell lung cancer whose disease has not progressed after four cycles of platinumbased firstline chemotherapy and as a singleagent for the treatment of patients with locally advanced or metastatic nonsquamous nonsmall cell lung cancer after prior chemotherapy.
Key words: pemetrexed - pyrimidine antifolate - malignant pleural mesothelioma - nonsmall cell lung cancer

 


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