Vincristine revisited

https://doi.org/10.1016/S1040-8428(98)00023-7Get rights and content

Section snippets

  • 1.

    Introduction

  • 2.

    Origin and history

  • 3.

    Structure

  • 4.

    Clinical indications

    • 4.1.

      Pediatric malignancies

    • 4.2.

      Malignancies in adults

  • 5.

    Side effects

    • 5.1.

      Neurotoxicity

    • 5.2.

      Non-neural side effects

  • 6.

    Mechanism of action and pathophysiology of neurotoxicity

    • 6.1.

      Mechanism of action

    • 6.2.

      Pathophysiology of neurotoxicity

  • 7.

    Pharmacokinetics

    • 7.1.

      Assays

    • 7.2.

      Plasma pharmacokinetics

    • 7.3.

      Cellular pharmacology, tissue distribution and excretion

    • 7.4.

      Metabolism

    • 7.5.

      Pharmacokinetics and pharmacodynamics

  • 8.

    Drug resistance

    • 8.1.

      Mechanisms of resistance

    • 8.2.

      Clinical relevance of vincristine drug resistance

    • 8.3.

Origin and history

Vincristine is a naturally occurring alkaloid. It is present in minute quantities in the leaves of the periwinkle plant Catharanthus roseus (L.) G. Don of the family Apocynaceae. Formerly this plant was called Vinca rosea by Linnaeus (L. or Linn.) and Lochnera rosea (L.) by Reichenbach. The Catharanthus roseus originated in Madagascar. Vincristine is extracted from the leaves of the plant 1, 2.

Vincristine has been known for its medicinal properties since the seventeenth century. Extracts from

Structure

The molecular structure of vincristine is asymmetrical and dimeric, composed of a dihydroindole nucleus, vindoline, linked by a carbon–carbon bond to an indole nucleus, catharanthine (Fig. 1). Vincristine sulphate is the 1:1 sulphate salt of the alkaloid extracted from Catharanthus roseus. The empirical formula of vincristine sulphate is C46H56N4O10H2SO4. The molecular weight is 923.1 kDa 21, 22, 23.

Clinical indications

Vincristine has a wide range of clinical applications. Single agent response rates in various malignancies are summarized in Table 1. However, these response rates should be interpreted with caution because of heterogenicity of patient populations and dosage regimens. For contemporary combination chemotherapy protocols we indicate the specific contribution of vincristine where possible. Vincristine is used more frequently and more effectively in pediatric oncology than in adults with cancer.

Neurotoxicity

Neurotoxicity is the dose-limiting side effect of vincristine. Vincristine induced neurotoxicity causes a peripheral, symmetric mixed sensory-motor, and autonomic polyneuropathy. The neuropathy is more marked distally and in the lower extremities 12, 22, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91. Table 2 lists symptoms and signs of vincristine neuropathy, their characteristic time of onset and incidence. The inappropriate antidiuretic hormone syndrome (SIADH) may be seen early during treatment

Mechanism of action

Vincristine exerts many effects on cells, using a variety of mechanisms, including interference with microtubules function. At least some of these contribute to its antitumor effect. The most established mechanism by which vincristine inhibits tumor growth is its interference with the mitotic spindle microtubules resulting in inhibition of mitosis 3, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159. In vitro, vincristine induces apoptosis in tumor cells 160, 161,

Assays

Pharmacokinetic data on vincristine are scarce in part due to limitations of the analytical methods for measuring vincristine. The first pharmacokinetic studies in humans were performed with tritium labeled vincristine or radio-immuno-assays (RIA). However, both methods were not specific for the parent compound resulting in both vincristine parent drug and metabolites assayed together. Pharmacokinetic studies using tritiated-vincristine or RIA therefore should be interpreted with caution 107,

Mechanisms of resistance

Mechanisms involved in resistance to vincristine in vitro include decreased intracellular drug retention or availability in the scope of the multi drug resistance (MDR) phenotype and changes of the drug target tubulin 167, 244, 245, 246. Evidence of resistance to vincristine-related apoptosis is emerging 164, 247.

Vincristine resistance related to the expression of the MDR phenotype is well characterized. The general features of MDR apply to vincristine. Cell-lines resistant to vincristine due

Neuroprotective agents

The use of neuroprotective agents may decrease the clinical features of vincristine induced neuropathy. The potential for these agents to interfere with the cytotoxicity of vincristine requires further study before these agents can be used outside experimental settings. Table 4 summarizes most agents studied. Folinic acid, vitamins B1, B6 and B12 and gangliosides were promising in animal models, but did not protect against vincristine induced neuropathy in humans. Isaxonine had intolerable side

Summary and future directions

Many controversies and questions about vincristine persist, despite extensive clinical application over the past 30–40 years. Further research effort is required to maximize the therapeutic ratio of vincristine. The contribution of vincristine as a component of multi drug protocols require critical evaluation to avoid unnecessary exposure to unwanted side effects without survival benefit.

The mechanism of mitotic inhibition of vincristine is well known. New insights in its cytotoxic effects,

Reviewers

This paper was reviewed by Dr MA Jordan, University of California, Santa Barbara, CA, USA, Dr S Lowis, Bristol Hospital for Sick Children, Bristol UK, and Dr CR Pinkerton, Royal Marsden, Sutton UK.

Corrie Gidding studied at the Medical School, University of Limburg, The Netherlands. She is a clinical and research fellow in Pediatric Oncology at the Childrens Cancer Center, Gronigen, The Netherlands. Vincristine is the subject of her thesis. Part of the research of her thesis was done at St Judes Children’s Research Hospital, Memphis TN, USA, and at the Bill Walsh Cancer Laboratories of the Royal North Shore Hospital, Sydney, Australia.

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    Corrie Gidding studied at the Medical School, University of Limburg, The Netherlands. She is a clinical and research fellow in Pediatric Oncology at the Childrens Cancer Center, Gronigen, The Netherlands. Vincristine is the subject of her thesis. Part of the research of her thesis was done at St Judes Children’s Research Hospital, Memphis TN, USA, and at the Bill Walsh Cancer Laboratories of the Royal North Shore Hospital, Sydney, Australia.

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