parang - med chem of M-Phase specific agents

microtubules dynamics

• microtubules:

  • hollow tubes

  • polymeric heterodimers consisting of isotypes of 𝜶 and β-tubulin proteins

• these distinct but nearly identical 50-kd proteins lie adjacent to one another within the tubule

  • roll up to form an open, pipe-like cylinder akin to a hollow candy stick

tubulin polymerization

• during cell division, tubulin undergoes intense, sporadic, and alternating periods of structural growth and erosion

• these proteins alternatively polymerize (elongation) and depolymerize (collapse) through guanosine triphosphate- and Ca2⁺-dependent processes

• microtubules have a (+) end (GTP-bound tubulin) and a negative end (-)

• polymerization involves the addition of tubulin dimers to either end of the tubule, although the faster-growing (+) end is more commonly invovled

• polymerization results in tubular elongation, whereas depolymerization results in the shortening of the structure

• inhibiting the essential changes in microtubular structure results in mitotic arrest and apoptosis

mitosis inhibitors

• 2 general classes of mitosis inhibitors have historically been marketed for the treatment of cancer:

  • taxanes

  • vinca alkaloids

• other agnets:

  • epothiolone, ixabepilone

• anti-microtubule drugs can be classified into drugs that inhibit polymerization or inhibit microtubule collapse

sites of binding to antimicrotubule agents to microtubules

• laulimalide binding site = 𝜶-tubulin

• taxane & epothiolone binding site = β-tubulin (within in the lumen)

• colchicine binding site = 𝜶β tubulin heterodimer

  vinca binding site = 𝜶β tubulin heterodimer

taxanes

• bind to polymerized (elongated) β-tubulin at a speicifc hydrophobic receptor site located deep within the tubular lumen

• this promotes the elongation phase of microtubule dynamic instability at the expense of the shortening phase and inhibits the disassembly of the tubule into the mitotic spindle

  • interruption the normal process of cell division

  • the formation of large and dense structures known as asters, which contain stabilized microtubule bundles

taxane SAR

• chemically, diterpenoid taxanes consist of a 15-membered tricyclic taxane ring system fused to an oxetane (D) ring and contain an esterified β-phenylisoserine side chain at C₁₃

• the 3 marketed taxane antineoplastics differ in substitution pattern at C₁₃ (benzamido or t-butoxycarboxamido), C₁₀ (secondary alchol, acetate ester, or methoxy ether), and/or C₇ (secondary alcohol or methoxy ether)

• essential functional groups

  • C₁₃-isoserine side chain

  • benzoyl esters at C₂

  • acetyl esters at C₄

  • the intact oxetane ring

paclitaxel

• “the best-selling anticancer drug in history”

  • in combination with cisplatin as first-line therapy for advanced ovarian and non-small cell lung cancer

• solution (Taxol, Onxol) and albumin-bound (Abraxane) formulations

• paclitaxel is administered in a vehicle of 50% alcohol/50% Kolliphor EL, which can lead to enhanced risk of hypersensitivity rxns

  • generally kept at bay by antihistamine/corticosteroid pretreatment

• abraxane contains paclitaxel nanoparticles with 3-4% albumin, which does NOT require the hypersensitivity-inducing Kolliphor EL in its formulation, has been used in various solid tumors of the GI and genitorurinary tracts

• pazenir is also an albumin-bound paclitaxel nanoparticle approved in Europe

abraxane MOA

• paclitaxel in an albumin shell

• albumin facilitates transport of paclitaxel nanoparticles to tumor cells

combination of paclitaxel with capecitabine

• in combination with the fluorouracil prodrug capecitabine in anthracyclien-resistant MBC

• paxclitaxel’s ability to upregulate thymidine phosphorylase, one of the capecitabine’s activating enzymes, is the rationale behind the combination therapy

docetaxel

• the indications for docetaxel, as a rule, mirror those of paclitaxel, although docetaxel is NOT used in ovarian cancer

• it has greater water solubility than paclitaxel due to the presence of free C₁₀-OH group, and it is formulated with polysorbate 80 (tween) rather than with polyoxyethylated castor oil (Kolliphor EL)

• hypersensitivity reactions, while less likely, are still possible, and all patients should receive corticosteroid premedication

cabazitaxel

• the 7,10-dimethoxy analog of docetaxel

  • dramatically lowers affinity for P-gp, resulting in sustained retention in tumor cells along with a higher BBB penetration

  • shown efficacy in docetaxel-resistant cell lines where resistance was due to P-gp overexpression

• approved for use only in docetaxel-resistant metastatic prostate cancer

• like docetaxel, it is formulated with polysorbate 80 rather than the more hypersensitivity-inducing Kolliphor EL, although antihistamine/corticosteroid pretreatment is still recommended

major problems with taxanes

• low water solubility

  • this is particularly true of paclitaxel, which has a more lipophilic acetate moiety at C₁₀ compared to docetaxel’s more polar hydroxl group

• paclitaxel must be administered in a vehicle of 50% alcohol/50% polyoxyethylated caster oil (Cremophor EL)

  • lead to enhanced risk of hypersensitivity reactions (dyspnea, hypotension,…) in pts not pretreated with H1 antagonists and dexamethasone

• high P-gp-mediated cellular efflux of paclitaxel and docetaxel can result in drug resistance

• overexpression of efflux pumps (cabazitaxel isn’t susceptible to efflux pump action, unlike Paclitaxel or Docetaxel)

taxanes — mechanisms of resistance

• overexpression of efflux pumps

• tubulin mutations (microtubule stability and/or drug binding)

• tubulin/microtubule alterations (altered tubulin isotype expression, changes in MAPs)

• microfilament alterations (altered interactions between microtubules and microfilaments)

• anti-apoptotic and signaling factors

epothilones

• 16-membered macrolides

  • functional groups properly positioned to mimic critical tubulin-binding groups

• enhanced water solubility

• lack of P-gp affinity

• epothilone is more efficiently produced through fermentation

• higher antineoplastic potency

• like paclitaxel, it uses Kolliphor EL for solubilization, so prophylactic premedication to protect against hypersensitivity reactions is required

vinca alkaloids

vincristine, vinblastine, vinorelbine

• several alkaloids in Catharanthus roseus (periwinkle) have potent antimitotic activity

• in opposition to the taxoids, vinca alkaloids halt cell division by inhibiting polymerization

vinca alkaloids SAR

• composed of 2 polycyclic segments known as catharanthine (or velbanamine) and vindoline, both of which are essential for high-affinity tubulin binding

• differ in the length of the alkyl chain bridging positions 6’ and 9’ of the catharanthine moiety (methylene or ethylene), in the substituents at position 4 (olefin or tertiary alcohol), and in the N₁ vindoline indole nitrogen (methyl or formyl)

• vincristine resistance is mediated, in part, through P-gp

vinca alkaloid MOA

• half cell division by inhibiting polymerization

• they bind to the interface of 2 heterodimers on β-tubulin

• spiral aggregates, protofilaments, and highly structured crystals form, and the mitotic spindle ultimately disintegrates

• the loss of the directing mitotic spindle promotes chromosome “clumping” in unnatural shapes (balls and stars), leading to cell death

• of the 3 marketed vinca alkaloids, (vincristine, vinblastine, and vinorelbine), vincrinstine binds most tightly, whereas vinbalstine has the lowest affinity

erbulin mesylate

• sequesters tubulin dimers into nonproductive aggregates

• inhibits microtubule growth

• has NO effect on microtubule shortening

vinca alkaloid with the longest terminal half-life

vincristine —> results in a more prolonged tumor cell expsoure

vinca alkaloid resistance

is mediated, in part, through P-gp

Marqibo

liposomal formulation of vincristine

• sphingomylein- and cholesterol-based nanoformulation

• loading and retention of vincristine and slow drug release in the tumor environment

• broad-spectrum activity against hematological malignancies