they bind tightly to cellular microtubules and block their function
the place of binding is the microtubular protein tubulin, it specifically binds to both its subunits (α and β) during the S phase of the cell cycle
binding to tubulin terminates the formation of microtubules , it causes their depolymerization and dissolution of the mitotic spindle
the result is mitosis arrest
they also affect microtubules, which enable chemotaxis, migration, intracellular transport, organelle movement…
Side effects:
vincristine: neurotoxicity (the largest of the vinca alkaloids) - paresthesia on acres, impaired muscle reflexes, muscle tone, motor and paralytic ileus , skin reactions, hypertension or hypotension , cardiovascular disorders, optic nerve atrophy or cortical blindness, polyuria, dysuria, impaired ADH secretion , bronchospasm, alopecia (hair loss) is not common / in hematological malignancies
vinblastine: neurotoxicity (less)
vinorelbine: neurotoxicity (smallest), krátkodobá reverzibilní myelosuprese, minimální emetické působení, short-term reversible myelosuppression, minimal emetic effect, intravenous use may cause phlebitis / in breast cancer lung and haematological tumors
Microtubule hyperstabilization
Taxanes (paclitaxel, docetaxel)
cytostatics made from the plant alkaloid taxol from the bark of the tree Taxus brevifola (Pacific yew), currently obtained semisynthetically from a plant precursor obtained from the needles of the European yew Taxus baccate
it also binds to microtubules, but the binding place is different
taxane binding inhibits microtubule depolymerization, which normally occurs in the cell at the end of cell division (during the transition from metaphase to anaphase)
cells with undecomposed tubules cease to divide and grow
taxanes penetrate well into body cavities, or into the retinal fluid (effusion), do not penetrate the CNS, excretion by the hepatobiliary route
Side effects::
common: neutropenia , hypersensitivity reactions due to histamine release , cardiac arrhythmias, allergic reaction may progress to anaphylaxis , neurotoxicity, fluid retention, inflammation at the site of paravenous administration or during the infusion into which they were infused
paclitaxel: neurotoxicity (peripheral polyneuropathy), alopecia , emetogenic, mucositis, anorexia nervosa , joint, muscle pain, necrosis during paravenous leakage / breast and ovarial cancers
inhibits the enzyme dihydrofolate reductase, which is responsible for the reduction of folic acid to tetrahydrofolic acid
after its application, the concentration of tetrahydrofolate in the cell decreases sharply
tetrahydrofolate, a coenzyme-transfer monocarbon radical (methyl, formyl and methylene groups) that is needed for the synthesis of purine bases and for NK repairs
methylenetetrahydrofolate is further required for the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate
NA synthesis is then disrupted in several stages, but these mechanisms affect both tumor and healthy cells
however, tumor cells should be more affected because they have a more intense process of polyglutamylation (binding of glutamyl groups to methotrexate), polyglutamyl forms of methotrexate have a greater affinity for dihydrofolate reductase
the antidote is leucovorin-tetrahydrofolic acid
Methotrexate inhibited reaction (reduction of dihydrofolate to tetrahydrofolate)Side effects::
toxic manifestations mainly on endothelial and epithelial tissues (mucous membranes, skin), on the skin can cause photosensitivity, itching, rash, toxic skin reaction and very rarely Lyell's syndrome, alopecia, vomiting, diarrhea, toxic mucositis, intestinal bleeding, ulceration of the oral mucosa and whole gastrointestinal tract, toxic to the gonads, decrease in neutrophils and platelets, long-term administration of small doses can cause liver damage (fibrosis) osteoporosis , high doses have direct nephrotoxic activity / in osteogenic sarcoma, immunosuppressive indication is psoriasis , psoriatic and rheumatoid arthritis
tetrahydrofolic acid metabolite derivative (reduced forms of folic acid)
tetrahydrofolate source - does not require DHFR activity
it is used at high doses of methotrexate or with 5-FU (increasing the activity of some enzymes increases the effect) - cancer of GIT
Purine analogs
They act::
inhibition of adenosine deaminase – Pentostatin
thiopurines inhibit purine synthesis and metabolism – Merkaptopurine
Side effects:
myelosuppression, toxic mucosal damage, indigestion (stomatitis, diarrhea), reversible hepatotoxicity / in acute lymphocytic leukemia and other malignant lymphoproliferative diseases
Pyrimidine analogues
5-fluorouracil (5-FU), capecitabine, gemcitabine
inhibit thymidylate synthase (5-FU, Capecitabine) – cancer of GIT
inhibit DNA polymerase
inhibit ribonucleotide reductase (Gemcitabine) – cancer of pancreas
inhibit DNA methylation
Side effects:
5-FU: mucositis, myelosuppression, alopecia, photosensitivity, hand-foot syndrome, hyperpigmentation / cancer of lungs, breast and GIT
capecitabine: only rarely myelotoxicity and alopecia, nausea, vomiting, diarrhea
gemcitabine: myelosuppression, influenza symptoms, less often mucositis and hepatotoxicity, emetic potential is not significant, alopecia is not common during monotherapy, nephrotoxicity with proteinuria and hematuria, dyspnoea or bronchospasm are rare
Ribonucleotide reductase inhibitors
Hydroxyurea
a compound chemically similar to urea
in the cell the enzyme blocks ribonucleotide reductase, which is responsible for the conversion of ribonucleotides to the corresponding deoxyribonucleotides
block of this enzyme stops the production of deoxyribonucleotides
however, it also inhibits pyrimidine synthesis
hese mechanisms damage cells mainly in the S-phase
in addition to inhibiting topoisomerase II, it also acts intercalating
Doxorubicin, Epirubicin – breast cancer, ovarial cancer, hematological malignancies…
Substances acting by an alkylation or intercalation mechanism (throughout the cell cycle)
Alkylating agents
they contain reactive alkyl groups (electrophilic) in their structure, these electrophilic groups attack negatively charged (nucleophilic - electron-rich) parts of molecules
nucleophilic groups represent those places of molecules where there are oxygen, nitrogen or phosphorus atoms (these are amino groups, imidazole, carboxyl, sulfhydryl or phosphate groups)
the electrophilic group forms a nucleophilic covalent bond
alkylation of DNA causes many defects, detachment of the purine base, breaks in one or two strands of DNA, internal bonds in the chain or between chains, thus damaging the genetic information of the cell and if not repaired in time, the cell dies
the effectiveness of alkylating cytostatics is thus dependent on the activity of the repair mechanisms of individual cells
eg. cyclophosphamide – used in hematological malignancies, a strong immunosuppressant
Side effects:
in general: By being able to kill even slowly proliferating tumor cells, they also damage slow-proliferating hematopoietic stem cells, causing long-term and sometimes permanent damage. Furthermore, amenorrhea, oligospermia leading to permanent infertility, mutagenic and carcinogenic effects that can cause acute leukemia or myelodysplastic syndrome
they do not alkylate in the true sense of the word - they do not have an alkyl group - only a similar effect as alkylating agents
it binds to DNA to form intercalation bonds that prevent replication and repair processes
the basis of combined chemotherapeutic regimens of many solid tumors (sarcomas, ovarial cancers, lung cancers…)
Side effects:
cisplatin: highly nephrotoxic, impairs tubular function, manifested by decreased glomerular filtration and isolated Mg losses, which can lead to tetany, peripheral neuropathy and hearing damage, Corti organ damage is irreversible, hearing loss for high tones is common, optic nerve damage , cortical blindness or papillary edema are exceptional, emetogenic effect
karboplatin: less neurotoxic, hematopoietic depression, less ototoxicity, alopecia, less emetogenic, dermatitis, mucositis, allergic reactions, itchy skin, taste changes
oxaliplatin: sensory neuropathy (dysesthesia of limbs, face and mouth), swallowing disorders , nausea, vomiting, not nephrotoxic and ototoxic
