Therapeutic Cancer Principles

Therapeutic Principles

• Chemotherapy is the use of medications to halt the formation of cancer cells.

Neoadjuvant Therapy

• This treatment is provided before radical surgery to reduce tumor size.
• It is indicated for overly large tumors, including breast, colon, and lung cancers.

Adjuvant Therapy

• It serves as a supplementary treatment following radical surgery.
• Targets and eliminates tumor cells potentially remaining after surgery.

Palliative Care

• Aims to relieve symptoms and reduce suffering caused by cancer, without providing a cure.

Alkylating Agents

• There are six main agents in use:
  • Nitrogen mustards
  • Ethylenediamines
  • Alkylsulfonates
  • Nitrosoureas
  • Triazenes
  • Methylhydrazines
• Nitrogen mustards function by alkylating DNA.

Mechlorethamine

• Administered intravenously or topically as a gel or cream.
• It is a lyophilized powder for reconstitution, with a concentration of 10 mg per vial.
• The main use is for treating Hodgkin's lymphoma and other lymphomas.
• It forms reactive ethylene-imino ions, creating covalent bonds with DNA's nitrogenous bases, particularly guanine at the N7 position.
• Causes the formation of intra- and inter-strand cross-links in DNA
• Affects replication and transcription, leading to cellular apoptosis.
• Side effects include nausea, vomiting, myelosuppression, leukopenia, thrombocytopenia, alopecia, anorexia, thrombophlebitis, maculopapular rash, and prolonged amenorrhea.

Cyclophosphamide

• Oral tablets are available in 25 mg and 50 mg doses.
• Intravenous vials are available in 200 mg, 500 mg, 1 g, and 2 g doses for reconstitution and IV administration.
• Mechanism of Action: Activated in the liver, it alkylates DNA at the guanine N7 position.
• It forms cross-links that block DNA replication, inducing apoptosis in rapidly dividing cells.
• The medication has immunosuppressive effects.
• Adverse effects: Myelosuppression (neutropenia, anemia, thrombocytopenia), nausea, vomiting, hemorrhagic cystitis, alopecia, and risk of infertility.

Ifosfamide

• Presented as a vial for intravenous administration (IV), available in 1g, 2g, and 3g powder for reconstitution.
• Mechanism of Action: activated in the liver, alkylates DNA at the guanine N7 position.
• Forming cross-links that block replication and transcription, induces apoptosis.
• Metabolites include acrolein, which causes hemorrhagic cystitis; and chloroacetaldehyde which leads to neurotoxicity.
• Adverse reactions: Hemorrhagic cystitis (preventable with MESNA), myelosuppression, neurotoxicity, nausea, vomiting, alopecia, risk of infertility.

Melphalan

• Mechanism of Action: Alkylation of DNA at the guanine N7 position, forming cross-links between and within DNA strands.
• Blocks replication and transcription, inducing apoptosis in tumor cells.
• Adverse Effects include myelosuppression, nausea, vomiting, mucositis, alopecia, gastrointestinal toxicity, and risk of secondary leukemia.

Cisplatin

• Administered intravenously, available in vials of 50 mg, 100 mg, and 200 mg.
• Mechanism of Action: Forms cross-links in DNA, preventing its replication and transcription, leading to cancer cell death.
• The drug enters cells and releases platinum (Pt2+), alkylating DNA mainly at guanine (N7), forming intra- and inter-strand cross-links and inhibiting DNA replication and transcription, inducing apoptosis in tumor cells.
• Side effects include nephrotoxicity, ototoxicity, myelosuppression, nausea, vomiting, neurotoxicity, and allergic reactions.

Carboplatin

• Administered intravenously, available in vials of 150 mg, 300 mg, and 450 mg as a solution for infusion.
• Mechanism of Action: Forms reactive complexes and binds to DNA, inhibiting DNA synthesis and inducing apoptosis.
• Adverse effects: Thrombocytopenia, nausea, vomiting, allergic reactions, fatigue, loss of appetite, renal toxicity, and peripheral neuropathy.

Oxaliplatin

• Available in vials of 50 mg/25 ml and 100 mg/50 ml.
• Mechanism of Action: Forms cross-links in DNA and inhibits DNA replication and transcription, affecting microtubules.
• Adverse effects: Peripheral neuropathy, myelosuppression, nausea, vomiting, and diarrhea.

Methotrexate

• Leucovorin can be used at high doses to rescue cells from its toxic effects.
• Glucarpidase is used to treat the toxicity of methotrexate.
• Attenuation of toxicity requires folate and vitamin B12.

Antimetabolites

• These work by inhibiting dihydrofolate reductase (DHFR).
• A key enzyme in purine and thymidylate nucleotide synthesis, essential for DNA replication and cell proliferation.
• Side effects include myelosuppression and gastrointestinal toxicity, leading to neutropenia, anemia, thrombocytopenia, nausea, and vomiting.
• Other side effects include diarrhea, stomatitis, skin eruptions, itching, and photosensitivity.

5-Fluorouracil

• A pyrimidine analog administered as an injectable solution and converted into 5-fluorodeoxyuridine monophosphate (FdUMP).
• FdUMP binds to and inhibits thymidylate synthase, preventing dUMP conversion to dTMP, reducing thymidine production essential for DNA replication.
• Adverse effects: Nausea, mucositis, diarrhea, myelosuppression, and hand-foot syndrome.

Capecitabine

• Administered orally as tablets (150 mg and 500 mg, coated), typically divided into two daily doses.
• It is converted into 5-FU in tumor tissue.
• The drug inhibits thymidylate synthase, thus blocking DNA synthesis.
• The incorporation induces instability and cell death.
• Severe hand-foot syndrome and diarrhea are common side effects, along with nausea, vomiting, stomatitis, neutropenia, anemia, and thrombocytopenia.

Cytarabine

• As an injectable solution, available in vials of 100 mg, 500 mg, 1 g, and 2 g.
• It is converted into Ara-CTP (cytarabine triphosphate) and incorporated into DNA instead of normal cytidine.
• Drug inhibits DNA polymerase, stopping DNA replication and cell division.
• It interferes with DNA repair, inducing apoptosis in tumor cells.
• Side effects can include myelosuppression, gastrointestinal issues, pulmonary edema, and dermatitis.

Gemcitabine

• Inhibits DNA polymerase
• Presented as a lyophilized powder for reconstitution in vials of 200 mg, 1 g, or 2 g.
• Drug is phosphorylated intracellularly into active forms, a diphosphate, and a triphosphate.
• Gemcitabine triphosphate incorporates into DNA, blocking DNA chain elongation, while the diphosphate inhibits the enzyme, reducing the availability of deoxynucleotides needed for DNA synthesis.
• Common side effects include myelosuppression, hepatic toxicity, and a syndrome similar to leucoencephalopathy.

Inhibitors of Topoisomerases

• Topotecan is available as an injectable solution in vials of 4 mg/4 mL and as oral capsules of 0.25 mg and 1 mg.
• Action: Inhibits topoisomerase I, preventing DNA strand relaxation by forming a stable complex with the enzyme. This generates single-strand DNA breaks that interfere with cell replication.
• Action: Induces apoptosis in proliferating cells, mainly affecting tumor cells.
• Common side effects: Severe neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea or constipation, stomatitis, alopecia, and flu-like symptoms.

Irinotecan

• Action: Converted into its active form (SN-38) in the liver with inhibitory effects on topoisomerase I, which stops DNA unwinding for replication.
• Prevents DNA repair in dividing cells, causing damage and inducing apoptosis in tumor cells.
• Results in both early (cholinergic, treatable with atropine) and late diarrhea (treatable with loperamide). Other common side effects include neutropenia, anemia, and thrombocytopenia.

Dactinomycin

• Act as an antibiotic that inhibits transcription by affecting DNA and RNA synthesis.
• Binds between DNA base pairs, hindering RNA polymerase action.
• Side effects include myelosuppression, severe nausea and vomiting as well as stomatitis, mucositis, diarrhea, erythema and skin inflammation.

Daunorubicin

• An Anthracycline.
• Available in injectable vials of 20 mg and 50 mg.
• Mechanism of Action: Inhibits topoisomerase II, intercalates into DNA, generates free radicals, and alters cell membrane.
• Side effects can include dose-dependent cardiomyopathy, which requires monitoring with echocardiograms and ejection fraction tests; severe myelosuppression, nausea, vomiting, mucositis, and alopecia.

Doxorubicin

• Mechanism of Action: Inhibits topoisomerase II, causing double-strand DNA breaks to stop cell replication.
• Intercalates between DNA base pairs, hindering transcription and replication of genetic material, generates free radicals.
• Side effects: can lead to Cardiomyopathy, myelosuppression, nausea, vomiting, mucositis, stomatitis, alopecia, and acts as a potent vesicant potentially causing necrosis.

Rubidomicin

• An Anthracycline.
• Action: Inhibition of topoisomerase II, intercalation in DNA, and generation of free radicals.
• Side effects: cardiomiopathy, myelosuppression, nausea, vomiting, mucositis, and alopecia.

Mitoxantrone

• An Antracenediona.
• Comes as an injectable solution in vials containing 5 mg or 10 mg.
• Inhibit topoisomerase II, intercalate into DNA, and generate free radicals.
• Can result in cardiomiopathy, arrythmias, mielosupression, nausea and vomiting, alopecia.

Etoposide

• An Epipodofilotoxin.
• Available as injectable and oral solutions(capsules)
• Action: Inhibits an enzyme responsible for DNA repair and replications. This cause DNA breaks, cell death and inhibits tumor growth.
• *Side-effects -Mielosupression
  • Nausea and vomiting
  • Alopecia
  • • gastic toxicity (Toxicidad gástrica)
  • Allergic reactions

Teniposido

• Inhibiting enzyme in cell responsible for DNA unwinding that causes double breaks that precent celluar growth that leads to cellular death in affected cells
• Side effects
  • Mielosupression
  • Alopecia and hypotension
  • Nausea and Vomiting

Microtubule Inhibitors

• Vinblastina - injectable
• Vinorelbina - injectible
• Vincristina - injectable
• Eribulin - injectable

Vincristine

• It inhibit the polymerization in microtubules and prevent division, causing cancer

Paclitaxel

• (Taxano) paclitaxel- interferes with the normal breakage for divisions.
• Blocks cells and cause accumulation to grow more than cells.

Docetaxel

• Docetaxel (Taxano) microtúbulos in the cells
• Binds to cell that is prevent to division and cause abnorma growth
• Blocks cells during the part of cell division(mitosis)