.
Chemical structures of the Vinca alkaloids.
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The Vinca alkaloids are naturally occurring or semisynthetic nitrogenous bases extracted from the pink periwinkle plant Catharanthus roseus G. Don.17–31 The early medicinal uses of this plant led to the screening of these compounds for their hypoglycemic activity, which was of little importance compared to their cytotoxic effects. In early studies in rodents, the Vinca alkaloids produced myelosuppression and increased the survival of animals bearing a transplantable lymphocytic leukemia, which redirected the development of these agents.17,18 Many Vinca alkaloids have been extensively evaluated, but only vincristine (VCR), vinblastine (VBL), and vinorelbine (VRL) are approved for use in the United States.
Chemical structures of the Vinca alkaloids.
), an indole nucleus (catharanthine), and a dihydroindole nucleus (vindoline), joined together with other complex systems. Structurally, VCR and VBL are identical except for a single substitution on the vindoline nucleus, where VCR and VBL possess formyl and methyl groups, respectively. Although this minor difference does not fundamentally alter the mechanism of action and tubulin-binding properties of these agents, the antitumor and toxicologic profiles of VCR and VBL differ significantly.17–24 VCR is used more commonly to treat pediatric malignancies, which likely reflects a combination of the higher level of sensitivity of pediatric malignancies to VCR and to the better tolerance of higher VCR doses in children. In both children and adults, however, VCR is an essential component of the chemotherapy regimens used to treat acute lymphocytic leukemia, lymphoid blast crisis of chronic myeloid leukemia, and both Hodgkin and non-Hodgkin lymphomas. VCR also plays a role in some multimodality therapies of Wilms tumor, Ewing sarcoma, neuroblastoma, and rhabdomyosarcoma, as well as in the treatment of multiple myeloma and small-cell lung cancer in adults. On the other hand, VBL has been a mainstay component of chemotherapy regimens for germ cell malignancies and some types of advanced lymphomas. On a historical note, VBL has also been used alone or in combination with other agents to treat Kaposi sarcoma and bladder, breast, and some types of brain malignancies.
Desacetyl vinblastine (vindesine; VDS), initially identified as a metabolite of VBL, was introduced in the 1970s.17–21 VDS is available only for investigational purposes in the United States, but is registered elsewhere. The agent was principally evaluated in combination with other agents, particularly cisplatin and/or mitomycin C, in treating non-small-cell lung cancer, but it has also demonstrated consistently favorable results in several hematologic and solid malignancies.20,21 The semisynthetic VBL derivative vinorelbine (5′-norhydro VBL; VRL), which is structurally modified on its catharanthine nucleus, resulting in substantially greater lipophilicity as compared to the other Vinca alkaloids, is approved in the United States for treating non-small-cell lung cancer as either a single agent or in combination with cisplatin, and has been registered to treat patients with advanced breast cancer elsewhere.22–25 VRL has also demonstrated anticancer activity in advanced ovarian carcinoma and lymphoma; however, a unique role in the therapy of these malignancies has not been defined.
Although the Vinca alkaloids produce a wide range of biochemical effects in cells and tissues, the principal mechanisms of cytotoxicity relate to their interactions with tubulin and disruption of microtubule function, particularly of microtubules comprising the mitotic spindle apparatus, leading to metaphase arrest.26–31 However, they are also capable of many other biochemical activities that may or may not be related to their effects on microtubules, including inhibiting synthesis of proteins and nucleic acids, elevating oxidized glutathione, altering lipid metabolism and membrane lipids, elevating cyclic adenosine monophosphate (cAMP), and inhibiting calcium-calmodulin- regulated cAMP phosphodiesterase.32 Many of the effects that do not involve microtubule disruption occur only after treatment of cells with clinically irrelevant doses of the Vinca alkaloids, whereas nanomolar concentrations induce typical antimicrotubule effects. Additional support of antimicrotubule actions, or more specifically, antimitotic actions, as being the principal cytotoxic effect of the Vinca alkaloids is that the dissolution of the mitotic spindle apparatus, appearance of mitotic figures, and cytotoxicity strongly correlate with both the duration and concentration of drug treatment.33 Nevertheless, the Vinca alkaloids and other antimicrotubule agents also affect both nonmalignant and malignant cells in the nonmitotic cell cycle, which is not surprising because microtubules are involved in many nonmitotic functions.
The Vinca alkaloids bind to binding sites on tubulin that are distinct from those of the taxanes, colchicine, podophyllotoxin, and GTP.3–6,8,26–31 Binding is rapid and readily reversible. Available evidence supports the existence of two Vinca alkaloid binding sites per mole of tubulin dimer.3–6,8 The Vinca alkaloids bind to their binding sites in intact microtubules with different affinities depending on whether the binding sites are located at the microtubule ends or situated along the microtubule surface.3–6,8 There are approximately 16 to 17 high-affinity binding sites per microtubule (Kd, 1 to 2 μmol) located at the ends of each microtubule. Binding of the Vinca alkaloids to these sites disrupts microtubule assembly, whereas the main effect of low drug concentrations is to decrease the rates of both growth and shortening at the assembly (plus) end of the microtubule, which, in effect, produces a “kinetic cap” and suppresses function.3–6,8,26–31 The potent kinetic suppression of tubulin exchange that occurs at low Vinca alkaloid concentrations (< 1 μmol) is caused by drug binding at the high-affinity sites at the microtubule end. This action suppresses dynamic instability, which increases the time that microtubules spend in a state of attenuated activity, neither growing nor shortening. The disruptive effects of the Vinca alkaloids on microtubule dynamics, particularly at the ends of the mitotic spindle, which leads to metaphase arrest, occur at drug concentrations below those that decrease microtubule mass. There are also one to two low-affinity binding sites per mole of tubulin dimer (Kd, 0.25 to 3.0 mmol) along the microtubule surface.3–6,8,30,31 Binding of the Vinca alkaloids to these sites appears to be responsible for the splaying of microtubules into spiral aggregates or spiral protofilaments, which leads to microtubule disintegration. This effect occurs at high drug concentrations (> 1 to 2 μmol) by a self-propagated mechanism, initially involving drug binding to a limited number of sites, which progressively weakens the lateral interactions between the protofilaments, thereby exposing new sites. Spiral protofilaments may then associate to form paracrystals.
The precise mechanisms that lead to cell death following treatment with the Vinca alkaloids are not entirely understood, but it is likely that most are similar to those that have been elucidated for the taxanes and involve the actions of genes such as p53, bcl-2, and bcl-x, and gene products that trigger programmed cell death or apoptosis following disruption of microtubule dynamics and cell-cycle traverse (see sections on “The Taxanes: Mechanisms of Action” and “The Taxanes: Mechanisms of Resistance” later in this chapter).33–41 In some cells, induction of caspase activity appears to be involved.36 Both the Vinca alkaloids and taxanes disrupt various signaling pathways that lead to apoptosis including the c-Jun N-terminal kinase/stress-activated protein kinase cascade.35,36 Drug-induced apoptosis is not dependent on the presence of an intact p53 checkpoint because the sensitivity of isogenic cell lines differing only in p53 status are similar.38 The loss of p21, a protein that modulates entry into M phase at the G2-M checkpoint, may enhance the sensitivity of tumor cells to both the Vinca alkaloids and taxanes, possibly by hastening entry of drug-damaged cells into mitosis. Low doses of deoxyribonucleic acid (DNA)-damaging agents, such as doxorubicin, decrease sensitivity to these antimicrotubule agents in p21-competent cells by induction of the checkpoint protein, and sensitivity can be restored in these cells by transfection of functional p21, even in the absence of p53.39,40 However, such phenomena relating to Vinca and taxane sensitivity in the clinic have not been defined. The antimicrotubule agents also activate Ras and a mitogen-activated kinase, ASK-1 (apoptosis signalregulating kinase), suggesting that other pathways may be involved as well, and that the disruption of the microtubule network is important in signaling of an apoptotic response.41
The Vinca alkaloids and other microtubule disrupting agents inhibit malignant angiogenesis in vitro. For example, VBL concentrations ranging from 0.1 to 1.0 pmol/L blocked endothelial proliferation, chemotaxis, and spreading on fibronectin, all essential steps in angiogenesis,42 but other normal fibroblasts and lymphoid tumors were unaffected at these minute concentrations. In combination with antibodies against vascular endothelial growth factor, low doses of VBL significantly augmented antitumor response, even in tumors resistant to direct cytotoxic effects of the drug.43 In these experiments, the combination of drug and antibody produced early and marked endothelial necrosis, followed by tumor regression. Whether these antiangiogenic effects play a role in clinical responses to the Vinca alkaloid class of drugs remains unanswered.
It is clear that the differential sensitivities and effects of the Vinca alkaloids against various tissues in vivo are not based on disparate mechanisms, as a similar mechanism of tubulin disruption appears to be principally involved.32,33,35,44–52 The differential sensitivities of various tissues appears to be multifactorial. One of the most likely explanations is that each tissue type has a distinct tubulin isotype composition and Vinca alkaloid sensitivity is, in part, dependent on the tissue profile of tubulin isotypes. Other putative factors include differences in the tissue content of cofactors such as MAPs and GTP that may influence drug interactions with tubulin.52
Variability in cellular permeation and retention may also influence the formation and stability of Vinca alkaloid-tubulin complexes.51–54 The Vinca alkaloids are rapidly taken up into cells and then accumulate intracellularly, with intracellular to extracellular concentrations ratios as high as 5- to 500-fold, depending on the cell type. In murine leukemia cells, the intracellular concentrations of VCR are 5- to 20-fold higher than the extracellular concentrations, and ratios ranging from 150- to 500-fold have been reported with other Vinca alkaloids.55 There are also marked differences in cellular uptake and retention between the Vinca alkaloids, the latter of which may relate to potency.44,56,57 For example, VRL is more rapidly taken up and metabolized than other Vinca alkaloids in isolated human hepatocytes,54,55and the greater potency of VCR during exposures of short duration compared to VBL was related to the greater cellular retention of VCR in another model system.44,47,52,56 Overall, the most important determinant of the rates of drug accumulation and retention is lipophilicity.44,52–59 The differences in the catharanthine ring of VRL renders it a more lipophilic agent and increases its retention in tissues, which may explain why it is more effective at disrupting the microtubules of the mitotic spindles as compared to axonal microtubules. The differential effects of the Vinca alkaloids on axonal microtubules related to cellular retention and lipophilicity may explain why VRL treatment is associated with less neurotoxicity than the other Vinca alkaloids.47,48
Although the cellular entry of the Vinca alkaloids was widely believed to be through both energy-dependent and temperature-dependent transport processes, temperature-independent nonsaturable mechanisms, analogous to simple diffusion, likely account for the majority of drug transport, whereas temperature-dependent saturable processes are less important.52–55 Both drug concentration and duration of treatment are important determinants of both drug accumulation and cytotoxicity, but the preponderance of available information indicate that drug exposure above a critical threshold concentration is the most important determinant.56
Several mechanisms of cellular resistance to the Vinca alkaloids have been characterized in tissue-culture experiments. Although the clinical relevance of these mechanisms is not entirely known, the antitumor spectrum and patterns of cross-resistance in the clinic that would be expected based on preclinical data suggest that several mechanisms are relevant.58–60 In nearly all preclinical models, Vinca alkaloid resistance is associated with cross-resistance to a multitude of structurally bulky natural product antitumor agents with variable mechanisms of action.58–62 This profile of cross-resistance properties typifies the “classic” pleiotropic or multidrug resistant (MDR) phenotype that can be either innate (primary) or acquired.61 MDR mediating proteins include permeability glycoprotein (Pgp), multidrug resistance protein (MRP), lung resistance protein (LRP), and MXR1/BCRP/ABCP, which are overexpressed in resistant cells and function as drug efflux pumps and binding proteins.61 The best characterized mechanism is mediated by the 170-kDa Pgp drug efflux pump in the plasma membrane, which is encoded by the mdr1 gene and results in decreased drug accumulation.61 Pgp, an adenosine triphosphatase (ATPase), functions to bind and extrude the Vinca alkaloids from the tumor cell in a process that requires energy in the form of adenosine triphosphate (ATP). The MDR phenotype also confers varying degrees of cross-resistance to other structurally bulky natural products such as the taxanes, anthracyclines, epipodophyllotoxins, and colchicine; however, resistance is most prominent against the principal agent in which selection pressure was established in vitro (see Chapter 48, “Drug Resistance and its Clinical Circumvention”). There is evidence that the amino acid sequence and antigenicity of the specific Pgp associated with resistance to the Vinca alkaloids differs slightly from Pgp of cells selected for resistance to Pgp substrate natural products such as colchicine and paclitaxel.61–64 These proteins also undergo posttranslational modifications, including N-glycosylation and phosphorylation, resulting in further structural diversity, which may explain the greater degree of resistance for the specific agent in which resistance was selected against, as well as the variable degrees of resistance to agents aside from that specific agent.65 The composition of membrane glycoproteins and gangliosides in VCR-resistant cells is demonstrated to be different from wild-type cells, which may have functional significance.66,67 The clinical ramifications of these mechanisms are not entirely known. In one study in childhood acute lymphoblastic leukemia (ALL), VCR resistance measured in vitro did not correlate with Pgp overexpression.67
The expression of mdr1/Pgp is highly regulated. A variety of mechanisms and factors involved in the transcriptional regulation of mdr1 expression have been reported, as have studies pertaining to the posttranslational regulation of Pgp function.68–70 Drugs and modulators that are Pgp substrates or inhibitors, as well as a multitude of DNA-damaging agents that are commonly used in our arsenal against cancer, may also induce expression of mdr1/Pgp.61,71 Additionally, modulation of the cell-cycle checkpoint protein p53 affects mdr1 expression and, therefore, may regulate the expression of the MDR phenotype.72
MDR can be reversed in vitro by a multitude of Pgp substrates and membrane active agents that have distinctly different structural and functional characteristics, such as the calcium channel blockers, calmodulin inhibitors, detergents, progestational and antiestrogenic agents, antibiotics, antihypertensives, antiarrhythmics, antimalarials, and immunosuppressives.61 These agents bind directly to Pgp, thereby blocking the efflux of the cytotoxic drugs and increasing intracellular drug concentrations. The role of MDR modulators has also been a source of contemporary interest in reversing and/or preventing drug resistance, but the interpretation of clinical studies of resistance modulation has been confounded by the fact that MDR modulators also enhance drug uptake in normal cells, decrease biliary elimination and drug clearance, and lead to enhanced toxicity.61,73 Overall, strategies aimed at reversing resistance to the Vinca alkaloids in the clinic with pharmacologic modulators of MDR have been disappointing to date.
MDR can also be conferred by the 190-kDa MDR protein, MRP1, which can function like an ATP-dependent drug transporter (see Chapter 48, “Drug Resistance and its Clinical Circumvention”).61 Transfection of MRP1 complementary deoxyribonucleic acid (cDNA) confers resistance to the Vinca alkaloids, anthracyclines, and etoposide, and results in reduced drug accumulation. Unlike Pgp-transfected cells, the cells transfected with MRP-1 demonstrate no or marginal resistance to colchicine and paclitaxel. In addition to MRP1, five human additional subfamilies have been identified, including MRP2 (cMOAT [canalicular multispecific organic anion transporter]), MRP3 (MOAT-D), MRP4 (MOAT-B), MRP5 (MOAT-C), and MRP6 (MOAT-E). Several of these subfamilies, most notably MRP2, can also confer resistance to various types of chemotherapeutic agents, including the Vinca alkaloids, methotrexate, camptothecins, etoposide, cisplatin, and anthracyclines; however, the different subfamilies appear to confer distinct, but overlapping, drug-resistance profiles.
MXR1, also known as BCRP or ABCP, is another distinct ATP-binding cassette, energy-dependent efflux protein whose overexpression has been found in tumor cells resistant to topotecan or mitoxantrone (see Chapter 48, “Drug Resistance and its Clinical Circumvention”).61 Transfection of MXR1/BCRP/ABCP into drug-sensitive tumor cells confers resistance to mitoxantrone, doxorubicin, daunorubicin, and topotecan, but not to paclitaxel, VCR, or cisplatin. Interestingly, some Pgp inhibitors that are currently in development have the potential to inhibit multiple transporter proteins and may increase drug sensitivity in MDR cells that do not express Pgp. Other agents that have been demonstrated to be effective inhibitors of several drug transporters may be attractive developmental candidates because MDR is often associated with the overexpression of multiple ATP-binding cassette transporter proteins.
Structural and functional alterations in α- and β-tubulins, resulting from either genetic mutations, posttranslational modifications, or differential expression of tubulin isotypes have also been identified in tumor cells with acquired resistance to the Vinca alkaloids.58–60,74–76 Acquired resistance to the Vinca alkaloids that result in increased microtubule stability is also associated with increased expression of MAPs, particularly MAP4.59 In any case, these mutations and alterations in tubulin and MAPs generally result in either decreased drug binding affinity or increased resistance to microtubule disassembly. Furthermore, these “hyperstable” microtubules are collaterally sensitive to the taxanes, which inhibit microtubule disassembly (see “The Taxanes: Mechanisms of Resistance”). Although such tubulin modifications have been demonstrated repeatedly in tumor cells that are continuously exposed to the Vinca alkaloids in vitro, the relevance of “hyperstable tubulin” caused by alterations in tubulins or MAPs is not known.
The Vinca alkaloids have been widely incorporated into combination chemotherapy regimens for palliative and curative therapies, based not only on their lack of cross-resistance with drugs that alkylate DNA, but also on their distinct mechanism of action. The lack of myelosuppression with VCR is an additional advantage that enables its use in full doses in combination with myelosuppressive agents in various chemotherapy regimens.
VCR has a broad antitumor spectrum and is an important component of combination chemotherapy regimens that commonly produce high remission rates in childhood and adult acute lymphocytic leukemias, Hodgkin and non-Hodgkin lymphomas, Wilms tumor, Ewing sarcoma, neuroblastoma, and rhabdomyosarcoma.17–20 VCR is also commonly used in combination with other antineoplastic agents in multiple myeloma, chronic lymphocytic leukemia, lymphoblastic crisis of chronic myelogenous leukemia, sarcomas, and small-cell lung carcinoma. In addition, VCR has been anecdotally reported to be useful in treating several nonmalignant hematologic disorders such as refractory autoimmune thrombocytopenia, hemolytic uremic syndrome, and thrombotic thrombocytopenia purpura.20
VBL has been an integral component of curative treatment regimens for testicular carcinoma and both Hodgkin and non-Hodgkin lymphomas (see Chapter 141d, “Hodgkin Disease,” and 141e, “Non-Hodgkin Lymphoma in Children”).20 Until recently, a regimen termed PVB, consisting of cisplatin, VBL, and bleomycin, was the standard treatment for advanced carcinomas of the testes.23 However, VBL has largely been replaced by etoposide in this combination, particularly in patients with favorable disease characteristics, because of the more favorable toxicity profile of the cisplatin-etoposide regimen. For Hodgkin lymphoma, VBL is often used in combination with doxorubicin, bleomycin, and dacarbazine (ABVD). This regimen is either administered alone or alternated with MOPP (nitrogen mustard, VCR, procarbazine, and prednisone), which is non-cross-resistant to ABVD.20 A MOPP/ABV hybrid regimen that includes both VCR and VBL has also been studied. Antineoplastic activity is also observed with VBL as a single agent or in combination with other antineoplastic drugs in carcinomas of the breast, bladder, and lung, Kaposi sarcoma, choriocarcinoma, terminal phase of chronic myelogenous leukemia, mycosis fungoides, Letterer-Siwe disease (histiocytosis X), and choriocarcinomas that are resistant to other chemotherapy agents.20 Infusions of VBL or VBL-loaded platelets have been effective in some cases of refractory autoimmune thrombocytopenia, because of its avidity to platelets.20
VDS is available only for investigational use in the United States. In some reports, response rates in non-small-cell lung cancer with combinations of VDS and cisplatin or mitomycin appear to be superior to those achieved with standard combinations or with either agent alone.20,21 In addition, antineoplastic activity has been seen in acute lymphocytic leukemia, blast crisis of chronic myeloid leukemia, malignant melanoma, pediatric solid tumors, and metastatic renal, breast, esophageal, and colorectal carcinomas; however, a unique role for VDS in oncology remains to be defined.21
VRL is approved in the United States as either a single agent or in combination with cisplatin for the initial treatment of patients with unresectable, advanced non-small-cell lung cancer.22,23 It has also demonstrated prominent antitumor activity in patients with advanced or metastatic breast cancer recurring following initial treatment and as a component of first-line regimens consisting of other non-cross-resistant chemotherapeutic agents and/or trastuzumab.22–25 VRL appears to be particularly well tolerated in elderly individuals, and its role as a component of first-line regimens in elderly patients with non-small-cell lung and breast carcinoma is under evaluation. In addition, VRL has also demonstrated prominent activity in patients with advanced Hodgkin and non-Hodgkin lymphomas and ovarian carcinoma, and its role in the treatment of these and other malignancies is currently being evaluated. Intriguing activity in cervical and prostate carcinoma has also been noted.
Information about the clinical pharmacology of the Vinca alkaloids, particularly VCR, VBL, and VDS that were largely studied decades ago, must be tempered by knowledge that sensitive, specific, and reliable analytic assays capable of measuring the minute plasma concentrations resulting from the administration of milligram quantity doses were not available. Pharmacologic studies were performed initially with radiolabeled drugs; however, interpretation of the results has been confounded by the chemical instability of these agents. Several Vinca alkaloids, particularly VCR and VBL, may undergo spontaneous degradation under mild conditions, forming degradative products that can be separated using high-pressure liquid chromatography (HPLC). Radiolabeled compounds coupled to HPLC was later used for improved separation of the various chemical moieties. More recently, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) methods using antisera capable of detecting picomolar drug concentrations have been developed. However, polyclonal antisera raised against the Vinca alkaloids cannot distinguish between the parent compounds and related derivatives, and, therefore, may not provide sufficient quantitative information about degradation products and metabolites. To meet the challenge, more refined RIA and ELISA methods using monoclonal antibodies with considerably greater sensitivity and specificity have been developed. Furthermore, advances in HPLC extraction (solid-phase and liquid-liquid) and detection (electrochemical and fluorescence) methods have made this one of the most feasible methods for separating Vinca alkaloids from their metabolites.
| Vincristine | Vinblastine | Vindesine | Vinorelbine | |
|---|---|---|---|---|
| Standard adult dose range (mg/m2/wk) | 1–2 | 6–8 | 3–4 | 15–30 |
| Pharmacokinetic behavior | Triphasic | Triphasic | Triphasic | Triphasic |
| Plasma half-lives | ||||
 α (min) | < 5 | < 5 | < 5 | < 5 |
| β (min) | 50–155 | 53–99 | 55–99 | 49–168 |
| γ (h) | 23–85 | 20–64 | 20–24 | 18–49 |
| Clearance (L/h/kg) | 0.16 | 0.74 | 0.25 | 0.4–1.29 |
| Primary route | Hepatic metabolism and biliary elimination | Hepatic metabolism and biliary elimination | Hepatic metabolism and biliary elimination | Hepatic metabolism and biliary elimination |
| Principal toxicity | Neurotoxicity | Neutropenia | Neutropenia | Neutropenia |
| Other toxicities | Constipation, SIADH | Alopecia, neurotoxicity, mucositis | Alopecia, neurotoxicity | Neurotoxicity, vomiting, constipation, mucositis |
SIADH = syndrome of inappropriate secretion of antidiuretic hormone.
VCR is rapidly distributed to the peripheral compartment following intravenous administration. There is extensive binding to both plasma proteins and formed blood elements, particularly platelets, which contain high concentrations of tubulin. This served as the rationale for using VCR-loaded platelets for treating disorders of platelet consumption such as idiopathic thrombocytopenia purpura.20 The platelet count inversely influences drug exposure.77 In contrast, penetration of VCR across the blood-brain barrier is poor, probably because of the molecule's large size and because it is an avid substrate for multidrug transporter pumps that maintain the integrity of the blood-brain barrier. Following administration of conventional doses (1.4 mg/m2) given as a brief infusion, peak plasma levels approach 0.4 μmol.18,20,55,78 Total VCR clearance is slow, which reflects avid tissue binding and slow release, and terminal half-lives in the range of 23 to 85 h have been reported.18,20,55–83 The wide variability in these values is likely caused by differences in the sensitivity of analytical assay methods and pharmacokinetic sampling schemes.
VCR is metabolized and excreted primarily by the hepatobiliary system. Seventy-two hours after the administration of radiolabeled VCR, approximately 12% of the radioactivity is recovered in the urine (50% of which consists of metabolites) and approximately 70% is recovered from feces (40% of which consists of metabolites).18–21,55,78–83 The nature of the VCR metabolites identified to date, as well as the results of metabolism studies in vitro, indicates that the agent is principally metabolized by hepatic cytochrome P450 CYP3A. There has been conflicting, albeit sparse, evidence that peak plasma concentration and systemic exposure are major pharmacologic determinants of VCR-induced neurotoxicity.18
The pharmacologic behavior of VBL is similar to that of VCR.20,55,77–87 Following rapid intravenous injection of VBL at standard doses, peak plasma drug concentrations are approximately 0.4 μmol/L. Like VCR, binding of VBL to plasma proteins and formed elements of blood is extensive. Furthermore, distribution is rapid, with half-life values of approximately 4 min and 1.6 h for α and β phases, respectively. Similar to VCR, tissue sequestration is prominent, with 73% of radioactivity retained in the body 6 days after treatment with the radiolabeled drug.20,55,84–88 Terminal half-life values ranging from 20 to 24 h have been reported. Like VCR, VBL disposition is principally through the hepatobiliary system. Fecal excretion of the parent compound is low, indicating substantial metabolism. The cytochrome P450 CYP3A isoform appears to be principally responsible for its biotransformation.55,81 Although the metabolic fate of VBL has not been fully characterized, 4-deacetyl VBL, or vindesine (VDS), which appears to be as active as the parent compound, is the principal metabolite of VBL.20,55
VDS is rapidly distributed to tissues; terminal half-life values range from 20 to 24 h.20,21,55,78,82,89–94 Its large volume of distribution, low renal clearance, and long terminal half-life suggest that VDS undergoes extensive tissue binding and delayed elimination. Similar to VCR and VBL, peak VDS concentrations range from 0.1 to 1.0 μmol/L following treatment with rapid intravenous injections, which are approximately 16-fold higher than those achieved with protracted infusions; however, prolonged periods of exposure above concentrations resulting in cytotoxicity in vitro (0.01 to 0.1 μmol) are readily achieved using protracted infusions (1.2 to 2.0 mg/m2/d for 2 to 5 days).21,55,83,90–92 Similar to the other Vinca alkaloids, VDS disposition is primarily by hepatic metabolism and biliary clearance, and the cytochrome P450 isoform CYP3A plays a major role in drug metabolism.21,55,89,93,94 Renal clearance is negligible, accounting for 1% to 12% of drug disposition.
The pharmacologic behavior of VRL is similar to those of the other Vinca alkaloids, with plasma concentrations declining in either a biexponential or triexponential manner.20,22–24,55,95–103 After intravenous administration, there is a rapid decay of VRL concentrations followed by much slower elimination phases (terminal half-life, 18 to 49 h). Plasma protein binding has been reported to range from 80% to 91%, with binding primarily to α1-acid glycoprotein, albumin, and lipoproteins.
VRL is widely distributed with extensive sequestration in virtually all tissues, except brain.20,22–24,55,95–103 The drug is also extensively bound to platelets. The wide distribution of VRL probably reflects the agent's lipophilicity, which is among the highest of the Vinca alkaloids. For example, VRL concentrations in human lung are 300-fold greater than plasma concentrations and 3.4- to 13.8-fold higher than lung concentrations achieved with VDS and VCR, respectively. Hepatic metabolism is the predominant mode of drug disposition.20,24, 55,97–103 Approximately 33% to 80% of the administered dose of VRL is excreted into the feces, whereas urinary excretion represents only 16% to 30% of total drug disposition, the majority of which is unmetabolized VRL. Studies in humans indicate that the cytochrome P450 isoenzyme CYP3A is principally involved in biotransformation.20,24,55,97–103 The predominant metabolites appear to be 4-O-deacetyl-VRL, 3,6-epoxy-VRL, and several hydroxy-VRL isomers. Although most metabolites are inactive, deacetyl-VRL may be as active as VRL. VRL is bioavailable following oral administration, however, the development of a suitable oral formulation is ongoing.96 Human studies of powder- and liquid-filled gelatin capsules show that bioavailability of the parent compound is 43% and 27%, respectively. Plasma concentrations peak within 1 to 2 h after oral treatment, and interindividual variability is moderate.
In cell culture, VCR or VBL enhances methotrexate accumulation in tumor cells, an effect mediated by a Vinca alkaloid-induced blockade of drug efflux; however, the minimal concentrations of VCR required to achieve this effect occur only transiently in vivo.104–106 The Vinca alkaloids also inhibit the cellular influx and cytotoxicity of the epipodyllotoxins in vitro, but the clinical ramifications of this effect are unknown. l-Asparaginase may reduce the hepatic clearance of the Vinca alkaloids, particularly VCR, which may result in increased toxicity. To minimize the possibility of this interaction, VCR should be given 12 to 24 h before l-asparaginase.
There are several reports of seizure activity following treatment with the Vinca alkaloids, which has also been associated with subtherapeutic plasma phenytoin concentrations.107–110 Reduced plasma phenytoin levels have been noted from 24 h to 10 days after treatment with both VCR and VBL. Because of the importance of the cytochrome P450 CYP3A isoenzyme in Vinca alkaloid metabolism, administration of the Vinca alkaloids with erythromycin and other inhibitors of CYP3A may lead to severe toxicity.110 Concomitantly administered drugs such as pentobarbital and H2-histamine antagonists may also influence VCR clearance by modulating hepatic cytochrome P450 metabolic processes.111–113 Another potential drug interaction may occur in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma who are receiving concurrent treatment with azidothymidine (AZT) and the Vinca alkaloids because the Vinca alkaloids may inhibit glucuronidation of AZT to its 5′-O-glucuronide metabolite.114
Although the Vinca alkaloids are quite similar from a structural standpoint, their toxicologic profiles differ significantly. All of the Vinca alkaloids induce a characteristic peripheral neurotoxicity, but VCR is most potent in this regard. The neurotoxicity is principally characterized by a peripheral, symmetric mixed sensory-motor, and autonomic polyneuropathy.24,26,27,113–117 The primary pathologic effect is axonal degeneration and decreased axonal transport, most likely caused by a drug-induced perturbation of microtubule function. At onset, only symmetric sensory impairment and paresthesia in a length-dependent manner (distal extremities first) is often encountered. Neuritic pain and loss of deep tendon reflexes may develop with continued treatment, which may be followed by foot drop, wrist drop, motor dysfunction, ataxia, and paralysis. Back, bone, and limb pains may occasionally occur. Electrophysiologic studies typically reveal normal nerve conduction velocities, however, diminished amplitude of sensory and motor nerve action potentials and prolonged distal latencies, resembling axonal degeneration, may be noted.18,20,113–117 Cranial nerves may also be affected rarely, resulting in hoarseness, diplopia, jaw pain, and facial palsies. The uptake of VCR into the brain is low, and central nervous system effects, such as confusion, mental status changes, depression, hallucinations, agitation, insomnia, seizures, coma, syndrome inappropriate secretion of antidiuretic hormone (SIADH), and visual disturbances, are infrequent. Laryngeal paralysis has also been reported. Acute, severe autonomic neurotoxicity is uncommon, but may arise as a consequence of high-dose therapy (greater than 2 mg/m2) or in patients with diminished drug clearance because of altered hepatic function.113–119 Toxic manifestations include constipation, abdominal cramps, paralytic ileus, urinary retention, orthostatic hypotension, and hypertension.
In adults treated with VCR, the neurotoxic effects may begin with cumulative doses as little as 5 to 6 mg, and manifestations may be profound after cumulative doses of 15 to 20 mg. Although it has been remarked that children are less susceptible to neurotoxicity than adults, and that the elderly are particularly prone, these apparent age-related differences may, in fact, be caused by previously inadequate dose calculation by body weight in children and adults and by body surface area in infants. In infants, VCR doses are calculated now according to body weight, which may be more accurate from a pharmacologic standpoint because of ubiquitous tissue distribution. Patients with antecedent neurologic disorders, such as Charcot-Marie-Tooth disease, hereditary and sensory neuropathy type I, Guillain-Barré syndrome, and childhood poliomyelitis, are highly predisposed to neurotoxicity.116 VCR treatment in patients with hepatic dysfunction or obstructive liver disease is associated with an increased risk of developing neuropathy because of impaired drug metabolism and delayed biliary excretion.
The only known effective intervention for Vinca alkaloid neurotoxicity is discontinuing treatment or reduction of the dose or frequency of drug administration. Although a number of antidotes, including thiamine, vitamin B12, folinic acid, pyridoxine, and neuroactive agents (eg, sedatives, tranquilizers, anticonvulsants), have been used, these treatments have not been clearly shown to be effective.18,20 Folinic acid protects mice against otherwise lethal doses of the Vinca alkaloids, and there are anecdotal reports of its successful use following VCR overdosage in man; however, prospective studies have never been performed. Suggested doses for folinic acid for the treatment of overdosage are 15 mg every 3 h for 24 h and then every 6 h for at least 48 h. Recent results with other protective agents appear more promising. In one randomized, double-blind trial, coadministration of glutamic acid and VCR was demonstrated to decrease neurotoxicity.120 The adrenocorticotropin (ACTH)4–9 analog ORG 2766 also protects against VCR-induced neuropathy in an animal model, and in a double-blind, placebo-controlled pilot study in cancer patients.20 Experimental results indicate that several other agents, such as nerve growth factor, insulin-like growth factor I, and amifostine, might alter the natural course of drug-induced neurotoxicity, but there has been no definitive evidence that these agents are effective in the clinic.
The manifestations of neurotoxicity are similar for all Vinca alkaloids; however, severe neurotoxicity is observed less frequently with VBL, VDS, and VRL, as compared to VCR.47,57 VRL has a lower affinity for axonal microtubules than either VCR or VBL, which seems to be confirmed by clinical observations.22–24,57,120 Mild to moderate peripheral neuropathy, principally characterized by sensory effects, occurs in 7% to 31% of patients, and constipation and other autonomic effects are noted in 30% of subjects, whereas severe toxicity occurs in only 2% to 3% of patients. Muscle weakness, jaw pain, and discomfort at tumor sites may also occur. In a study in patients with non-small-cell lung cancer randomized to treatment with either VRL alone, VRL plus cisplatin, or VDS plus cisplatin, the rate of severe neurotoxicity was lower in both the single-agent VRL and VRL plus cisplatin arms, than in the VDS plus cisplatin arm.121 Furthermore, the addition of cisplatin did not significantly increase the incidence of severe toxicity above that observed with VRL alone.
Neutropenia is the principal dose-limiting toxicity of VBL, VDS, and VRL. Thrombocytopenia and anemia are usually less common and less severe. The onset of neutropenia is usually 7 to 11 days after treatment, and recovery is generally by days 14 to 21. Myelosuppression is not typically cumulative. Although VCR is rarely associated with hematologic toxicity, severe myelosuppression has been observed in situations resulting in profoundly increased drug exposure (such as following inadvertent overdosages) and hepatic insufficiency.
Gastrointestinal toxicities, aside from those caused by autonomic dysfunction, may be caused by all the Vinca alkaloids.18,20,113,114,117,122 Gastrointestinal autonomic dysfunction, as manifested by bloating, constipation, ileus, and abdominal pain, occur most commonly with VCR or high doses of the other Vinca alkaloids. Mucositis occurs more frequently with VBL than VRL or VDS, and is least common with VCR. Nausea, vomiting, and diarrhea may also occur to a lesser extent. Pancreatitis has also been reported with VRL.123
The Vinca alkaloids are potent vesicants and may cause significant tissue damage if extravasation occurs. If extravasation occurs or is suspected, treatment should be discontinued immediately and aspiration of any residual drug remaining in the tissues should be attempted.124 The application of local heat and injection of hyaluronidase, 150 mg subcutaneously, in a circumferential manner around the needle site are thought to minimize both discomfort and latent cellulitis, perhaps by facilitating drug dispersion. Phlebitis may also occur along the course of an injected vein, with resultant acute inflammation followed by sclerosis. The risk of phlebitis may increase if veins are not adequately flushed after treatment. The incidence of phlebitis can be reduced with shorter administration durations.
Mild and reversible alopecia occurs in approximately 10% and 20% of patients treated with VRL and VCR, respectively. Acute cardiac ischemia, chest pains without evidence of ischemia, fever without an obvious source, acute pulmonary effects (alone or in combination with mitomycin C), Raynaud phenomenon, hand-foot syndrome, and pulmonary and hepatic toxicity have also been reported with the Vinca alkaloids.20,125–131 All of the Vinca alkaloids have been implicated as a cause of SIADH, and patients who are receiving intensive hydration are particularly prone to severe hyponatremia secondary to SIADH.18,20,132 This entity has been associated with elevated plasma levels of antidiuretic hormone and usually remits in 2 to 3 days. Hyponatremia generally responds to fluid restriction, as with hyponatremia associated with SIADH from other causes.
It is recommended that the Vinca alkaloids be administered by rapid intravenous injection, possibly through a running parenteral infusion. After treatment, flushing of the vein should be continued to prevent injection site reactions. Inadequate flushing may increase the risk of phlebitis, and, therefore, the catheter should not be removed before the vein is flushed.
VCR is commonly administered to children weighing more than 10 kg as a bolus intravenous injection at a dose of 1.5 to 2.0 mg/m2 weekly, although 0.05 to 0.65 mg/kg weekly is commonly used in smaller children. For adults, the conventional weekly dose is 1.4 to 2.0 mg/m2. A restriction of the absolute dose of VCR to 2.0 to 2.5 mg in children and 2.0 mg in adults, which is often referred to as “capping,” has been generally adopted based on early reports of substantial gastrointestinal toxicity in small numbers of patients treated at higher doses. However, there is very little pharmacologic or toxicologic evidence to support this practice, and available evidence suggests that it should be reconsidered, particularly in light of the wide interpatient variability in pharmacokinetic behavior and tolerance.133 There is significant interpatient variability in the clearance of VCR (as much as 11-fold), and some patients are able to tolerate much higher doses with little or no toxicity. Moreover, the safety and efficacy of treatment regimens that do not employ “capping” at 2.0 mg have been documented in adults.133 In any case, doses should not be reduced for mild peripheral neurotoxicity, particularly if the agent is being used in a potentially curative setting. Instead, doses should be modified for manifestations indicative of more serious neurotoxicity, including severe symptomatic sensory changes, motor and cranial nerve deficits, and ileus, until toxicity resolves. In clearly palliative situations, dose reductions, lengthening dosing intervals, or selecting an alternative agent may be justified in the event of moderate neurotoxicity. A routine prophylactic regimen to prevent the serious consequences of severe autonomic toxicity, particularly severe constipation, is also recommended.
The most commonly used schedule for VBL in combination chemotherapy regimens uses a rapid intravenous injection at a dose of 6 mg/m2 weekly. Approved dosing recommendations for weekly dosing are 2.5 and 3.7 mg/m2 for children and adults, respectively, followed by gradual escalation in increments of 1.8 and 1.25 mg/m2 weekly based on hematologic tolerance. It is recommended that weekly VBL doses of 18.5 mg/m2 in adults and 12.5 mg/m2 in children not be exceeded as a single agent; however, these doses are substantially higher than most patients can tolerate because of myelosuppression, even on less-frequent schedules of administration. Because the severity of leukopenia that may occur with identical VBL doses varies widely, VBL should probably not be given more frequently than once each week.
VDS has been administered intravenously on many schedules, including weekly and biweekly bolus and prolonged infusion schedules. The agent has also been given in fractionated doses as either an intermittent or a continuous infusion over 1 to 5 days. VDS is most commonly administered as a single intravenous dose of 2 to 4 mg/m2 every 7 to 14 days. Intermittent or continuous infusion schedules usually employ VDS doses of 1 to 2 mg/m2/d for 1 to 2 days, or 1.2 mg/m2/d for 5 days every 3 to 4 weeks.83
VRL is usually administered at a dose of 30 mg/m2 on a weekly or biweekly schedule as a 6- to 10-min intravenous injection through a side-arm port into a running infusion (alternatively, a slow bolus injection followed by flushing the vein with 5% dextrose or 0.9% sodium chloride solutions) or as a short infusion over 20 min.22–25 It appears that the more rapid infusions are associated with less local venous toxicity. Oral doses of 80 to 100 mg/m2 given weekly are generally well tolerated, but an acceptable oral formulation has not yet been approved. Other dosing schedules that have been evaluated include chronic oral administration of low doses, intermittent high doses, and prolonged intravenous infusion schedules.
Because of their remarkable vesicant properties, the Vinca alkaloids should not be administered intramuscularly, subcutaneously, intravesically, or intraperitoneally. Direct intrathecal injection of VCR and other Vinca alkaloids, which has occurred as inadvertent clinical mishaps, induces a severe myeloencephalopathy characterized by ascending motor and sensory neuropathies, encephalopathy, and rapid death.18,20,134,135
Although it has not been carefully evaluated, the major role of the liver in the disposition of the Vinca alkaloids implies that dose modifications should be considered for patients with hepatic dysfunction132; however, firm guidelines have not been established. A 50% dose reduction is often recommended for patients with total bilirubin levels between 1.5 and 3.0 mg/dL (50% dose reduction for bilirubin levels between 2.0 and 3.0 mg/dL is recommended for VRL), and at least a 75% dose reduction for plasma total bilirubin levels above 3.0 mg/dL. Dose reduction for renal dysfunction is not indicated.
