Pharmacology of Chemotherapy for Tumors in the Nervous System of Children

Mechanism of Action

Alkylating agents

• Temozolomide : Temozolomide is an alkylating agent prodrug that delivers a methyl group to the purine bases of DNA (O6-guanine; N7-guanine, and N3-adenine).
• Nitrosoureas (BCNU, CCNU): The alkylation of guanine, cytidine, and adenine and carbamylation by nitrosourea metabolites interferes with the cross-linking synthesis and function of DNA, RNA, and proteins.
• Platinums (cisplatin, carboplatin): These agents cause possible cross-linking of the DNA strands and interference with the function of DNA.
• Procarbazine: Procarbazine inhibits the transmethylation of methyl groups of methionine into t-RNA, resulting in the cessation of protein, RNA, and DNA synthesis.
• Ifosfamide: Ifosfamide is classified as an alkylating agent of the nitrogen mustard type. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis.
• Cyclophosphamide: Cyclophosphamide is an alkylating agent of the nitrogen mustard type. Its action is similar to that of ifosfamide.
• Thiotepa: Thiotepa’s activity occurs as a result of formation of an unstable ethylene immonium ion, which alkylates or binds with many intracellular molecular structures, including nucleic acids. Its cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis.

Alkaloids

• Vincristine: Vincristine arrests replicating cells at the metaphase stage through prevention of microtubule formation in the mitotic spindle.
• Vinblastine: Vinblastine inhibits microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.

Topoisomerase inhibitors

• Irinotecan: This agent prevents re-ligation of single-strand breaks when it binds to the topoisomerase 1-DNA complex. Its cytotoxic action is due to the damage in double-strand DNA when replication enzymes act on the formed ternary complex.
• Etoposide: Etoposide is a topoisomerase II inhibitor. It appears to act at the premitotic stage of cell division to inhibit DNA synthesis. It is cell cycle–dependent and phase-specific, with maximum effect on the S and G 2 phases of cell division.

Antimetabolites

• Methotrexate: Methotrexate interferes with DNA synthesis, repair, and cellular replication by inhibiting dihydrofolate reductase.

Agents targeting signaling pathways

• Bevacizumab: This agent is a recombinant, humanized monoclonal IgG1 antibody that binds to VEGF and inhibits the interaction of VEGF to Flt1 and KDR receptors on the surface of endothelial cells. In the process, it prevents the proliferation of endothelial cells and formation of new blood vessels.
• Everolimus: Everolimus forms a complex with the cytoplasmic FKBP-12: FKBP-12 complex binds to and inhibits the mammalian mTOR and phosphorylates P70 S6 ribosomal protein kinase (a substrate of mTOR). The phosphorylation of P70 S6 ribosomal protein kinase by the everolimus complex prevents protein synthesis and cell proliferation. Everolimus reduces the activity of S6 ribosomal protein kinase and eukaryotic elongation factor 4E-binding protein, inhibits the expression of hypoxia-inducible factor, and reduces VEGF expression.

Molecular/Genetic Factors

Alkylating agents

• Temozolomide: The primary cytotoxic metabolite resulting from the administration of temozolomide is O6-MeG. It can be removed by MGMT (direct repair) in tumors expressing this protein, or tolerated in MMR-deficient tumors. Thus, MGMT or MMR-deficiency confers resistance to temozolomide. Silencing of the MGMT gene is associated with a better prognosis in malignant glioma (20).

Uses for Agents by Histopathology

Alkylating agents

• Temozolomide and nitrosoureas: These agents have been the mainstay of chemotherapy for malignant gliomas.
• Platinums: Platinums have been a component of germ cell tumor regimens; carboplatin is the mainstay of LGG protocols.
• Lomustine, cisplatin, cyclophosphamide: These have been the main agents used for chemotherapy in conjunction with radiation for medulloblastomas.
• Thiotepa: Thiotepa is used as part of the submyeloablative consolidation chemotherapy for infants with malignant brain tumors and certain recurrent malignant brain tumors.

Alkaloids

• Vincristine: Vincristine has been a component of most brain tumor chemotherapy protocols.

Topoisomerase inhibitors

• Irinotecan: Irinotecan has been used particularly for recurrent malignant gliomas or medulloblastomas.
• Etoposide: Etoposide is a major component of induction and consolidative chemotherapy for malignant infant brain tumors. It is also part of germ cell tumor protocols.

Antimetabolites

• Methotrexate: Methotrexate has been used in infant protocols in an attempt to eliminate or diminish radiation exposure.

Agents targeting signaling pathways

• Bevacizumab: Bevacizumab is used to treat recurrent gliomas, and its use is being explored in clinical trials as part of first-line therapy for malignant gliomas and recurrent PNETs.
• Everolimus: This agent is used for progressive surgically unresectable giant cell astrocytomas.