The drug vincristine is used to treat many cancers. Apparently works by causing

Question

The drug vincristine is used to treat many cancers. Apparently works by causing microtubules to depolymerize. Vincristine use has many side effects, including loss of dividing cells and nerve problems. Explain why this might be so? The drug vincristine is used to treat many cancers. Apparently works by causing microtubules to depolymerize. Vincristine use has many side effects, including loss of dividing cells and nerve problems. Explain why this might be so? The drug vincristine is used to treat many cancers. Apparently works by causing microtubules to depolymerize. Vincristine use has many side effects, including loss of dividing cells and nerve problems. Explain why this might be so?

Explanation / Answer

For a quick answer to the question, please see the CONCLUSION and for detailed understanding see the other information provided

Firstly, what is Vincristine?

Vincristine belongs to the group of indole alkaloids (chemically they are dimeric compounds) obtained from periwinkle plant, Catharanthus roseus (also called as Vinca rosea). The side effects of vincristine specifically (and vinca alkaloids in general) were first demonstrated by Noble and co-workers, who reported granulocytopenia and bone marrow suppression in rats while testing their efficiency in treatment for diabetes mellitus.

Purified alkaloids caused regression of an acute lymphocytic leukemia in mice. Apart from vincristine the other vinca alkaloids include: vinblastine, vinleurosine, and vinrosidine. Vinblastine and vincristine are important clinical agents for treatment of leukemias, lymphomas, and testicular cancer.

Now, Let us look at its mechanism of action of Vincristine in detail (although it was mentioned in the question)

Mechanism of Action:

Vincristine is a cell-cycle–specific agent block cells in mitosis. The biological activity of the vincristine can be explained by their ability to bind specifically to tubulin and to block its ability to polymerize with -tubulin into microtubules.

Cell division is arrested in metaphase. In the absence of an intact mitotic spindle, duplicated chromosomes cannot align along the division plate. They disperse throughout the cytoplasm (exploded mitosis) or may clump in unusual groupings, such as balls or stars. Cells blocked in mitosis undergo changes characteristic of apoptosis.

CAUSE FOR NERVE PROBLEMS (NEUROLOGICAL TOXICITY)

Apart from microtubules role in the formation of mitotic spindles, they are also found in high concentration in the brain and are essential to other cellular functions such as movement, phagocytosis, and axonal transport. Side effects of the Vincristine, such as its neurotoxicity, may be due to disruption of these functions.

Out of all the vinca alkaloids, vincristine has predictable cumulative effects. Numbness and tingling of the extremities and loss of deep tendon reflexes constitute the most common and earliest signs and are followed by motor weakness. The sensory changes do not usually warrant an immediate reduction in drug dose, but loss of motor function should lead to a reevaluation of the therapeutic plan, and under most circumstances, discontinuation of the drug. Rarely, patients may experience vocal cord paralysis or loss of extraocular muscle function. High-dose vincristine causes severe constipation or obstipation. Inadvertent intrathecal vincristine administration produces devastating and invariably fatal central neurotoxicity, with seizures and irreversible coma

Other toxicities:

The clinical toxicity of vincristine is mostly neurological, as described above. The more severe neurological manifestations may be avoided or reversed by either suspending therapy or reducing the dosage upon occurrence of motor dysfunction. Severe constipation, sometimes resulting in colicky abdominal pain and obstruction, may be prevented by a prophylactic program of laxatives and hydrophilic (bulk-forming) agents.

Alopecia occurs in about 20% of patients given vincristine; however, it is always reversible, frequently without cessation of therapy. Although less common than with vinblastine, leukopenia may occur with vincristine, and thrombocytopenia, anemia, polyuria, dysuria, fever, and gastrointestinal symptoms have been reported occasionally. The syndrome of inappropriate secretion of antidiuretic hormone occasionally has been observed during vincristine therapy. In order to prevent hyperuricemia vincristine is coadministered with allopurinol.

Vincristine in standard doses, causes little reduction of formed elements in the blood. A syndrome of hyponatremia due to inappropriate secretion of antidiuretic hormone occurs rarely after vincristine administration

Just like any other anticancer drug, these have general toxicity on rapidly dividing healthy cells due to their inability to differentiate between cell division cycles of healthy and cancer cells which may lead to:

i. Bone marrow depression resulting in granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anaemia

ii. Oral mucosa is more susceptible to cytotoxic drugs (vincristine in this given case) due to high epithelial turnover. Gums and oral mucosa are subjected to trauma, breaches, inflammation and ulceration due to the use of anticancer drugs

iii. Gastrointestinal tract is also affected by use of antineoplastic drugs (vincristine here) which is manifested as diarrhoea, shedding of mucosa, haemorrhages

iv. Inhibition of gonadal cells results in oligozoospermia, impotency in males and inhibition of ovulation and amenorrhoea in female

v. Due to teratogenicity of the antineoplastic drugs, they also affect the fetus when given in pregnancy

CONCLUSION:

1. CAUSE FOR NERVE PROBLEMS: SINCE MICROTUBULES ARE ALSO IMPORTANT IN BRAIN CELLS AND OTHER NEURONAL FUNCTIONS AND VINCRISTINE BEING AN INHIBITOR OF POLYMERIZATION OF MICROTUBULES, IT RESULTS IN NEUROLOGICAL TOXICITY

2. JUST LIKE ANY OTHER ANTICANCER DRUGS, VINCRISTINE BEING UNABLE TO DIFFERENTIATE THE RAPIDLY DIVIDING HEALTHY CELLS AND CANCER CELLS, TARGET BOTH OF THEM, RESULTING IN LOSS OF HEALTHY DIVIDING CELLS

Other useful information about vincristine:

Pharmacological Actions of Vincristine

Vincristine is a standard component of regimens for treating pediatric leukemias, lymphomas, and solid tumors. In large-cell non-Hodgkin's lymphomas, vincristine remains an important agent, along with cyclophosphamide, doxorubicin, and prednisone. As mentioned previously, vincristine is more useful for remission induction in lymphocytic leukemia. Vincristine also is a standard component of a number of regimens used to treat pediatric solid tumors such as Wilms' tumor, neuroblastoma, and rhabdomyosarcoma.

Absorption, Fate, and Excretion (Pharmacokinetics)

The liver extensively metabolizes vincristine and its conjugates and metabolites are excreted in the bile. Only a small fraction of a dose is found in the urine unchanged. The elimination half-life is 20 hours

Therapeutic Uses:

Vincristine sulfate (Brand Names: ONCOVIN, VINCASAR PFS) used together with glucocorticoids is the treatment of choice to induce remissions in childhood leukemia; Hodgkin's disease or non-Hodgkin's lymphomas. Vincristine seems to be tolerated better by children than by adults, who may experience severe, progressive neurological toxicity.

Alternate solution to prevent Neurotoxicity: A liposomal formulation of vincristine appears to have less neurotoxicity and retains activity in patients who relapse after vincristine therapy. It has the expected pharmacokinetic advantage of slower elimination and greater tissue distribution as compared to the unmodified drug

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