Antimicrotubule agents

Tubulin-interactive agents, commonly known as 'spindle poisons' have a long history of use in cancer treatment. They act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are important structural units involved in a number of cellular activities, including formation of the mitotic spindle.

Agents that bind to tubulin can be categorized according to their main tubulin binding site:

♦ Vinca alkaloid binding site

♦ Colchicine binding site

♦ Rhizoxin/maytansine binding site

♦ Tubulin sulfhydryl groups

♦ A separate class of as yet uncharacterized binding sites

The table focusses on important anti-microtubule agents in pre-clinical and clinical development, grouped into families to summarize:

♦ Mechanism of action

♦ Major indications

♦ Administration

♦ Pharmacokinetic data for clinical practice

♦ Selected important information for the clinic

Tubulin is an important target for anti-cancer drug development; several anti-tubulin agents have significant anti-cancer activity in the clinic. Taxanes were the most encouraging development in anti-cancer chemotherapy of the 1990s; paclitaxel, when incorporated in a firstline chemotherapy regimen for advanced ovarian cancer leads to significant prolongation of survival, while docetaxel can make a small but significant impact on survival of metastatic breast cancer patients, even when given in a second- or third-line setting to heavily pre-treated patients.

Recent progress observed with taxanes has led to renewed interest in anti-microtubule analogues or drugs interacting with different sites on tubulin. In particular, agents with an improved pharmacological profile and/or activity in vinca/taxane-resistant cell lines are of interest. Several new anti-tubulin agents are in pre-clinical development.

Most of the basic research into drug resistance has involved using pairs of sensitive and resistant tumour cells derived from the same parental cell line, usually by serial passage in increasing concentrations of the drug under investigation. This is an artificial situation

Table 9.1 Anti-microtubule agents

Class of spindle poison Useful indications (mechanism of action)

Drug administration (IV doses in mg/m2)

Main toxicities

Pharmacokinetics and Comments of clinical metabolism interest

Vincristine (VCR) Leukaemias, 0.5-1.4 q 1-4 w

(destabilization of lymphomas,paediatric (total individual dose:

polymerised tubulin tumours,small-cell 2 mg) ((-tubulin)) lung cancer,multiple myeloma

Neuropathy

Metabolized in the liver

VCR induces multi-drug resistance (MDR) by P-glycoprotein (PgP). Mutations in a and ( tubulin proteins enhance stability against depolymerization.

Vinblastine (VBL) (same as VCR)

Lymphomas, germ cell 6-10 q 2-4 w tumours, Kaposi's sarcoma, breast cancer

Neutropenia, neuropathy

Metabolized in the liver

Neuropathy occurs less frequently than with VCR

Vindesine (VDS) same as VCR) prostate,

Non-small-cell lung 2-4 q 1-3 w cancer (NSCLC), breast cancer, lymphomas

Neutropenia, Metabolized in the liver Randomized trials (breast, neuropathy NSCLC, sarcomas, and melanoma) with VDS showed no advantage over treatments without VDS.

Vinorelbine (NVB) (same as VCR)

NSCLC, breast cancer

25-30 / w combinations: Neutropenia, cisplatin (NSCLC) and constipation, doxorubicin or 5FU neuropathy

(breast). Oral form in clinical development

Metabolized in the liver

Selective binding to the Tau family of microtubule — associated proteins ^ tubulin aggregation into spirals and paracrystals.

Class of spindle poison Useful indications (mechanism of action)

Drug administration (IV doses in mg/m2)

Main toxicities

Pharmacokinetics and Comments of clinical metabolism interest

NVB not active and associated with severe neurotoxicity in paclitaxed pre-treated breast cancer patients.

Paclitaxel (P) (microtubule stabilizer) (also anti-angiogenesis effect, disruption of Ki-Ras function, apoptosis induction by phosphorylation of bcl-2)

Ovarian, breast, and lung cancers (other tumours).Reproducible anti-tumour activity (response rate 15-25%) in platinum-resistant ovarian cancer stimulated further clinical development.

135 (24 h)-175 (3 h) q 3 w.Weekly schedule is under investigation. Combinations:mainly with cisplatin or carboplatin (ovary) and doxorubicin (breast)

Neutropenia, neurotoxicity

Metabolized in the liver. Cisplatin ^ P:severe neutropenia; P ^ doxorubicin: more mucositis than the reverse sequence.

Toxicities are sequence- and schedule-dependent. Steroid pre-medication is used to reduce hypersensitivity reactions.Water-soluble analogues and derivatives active in resistant cells of P are under development. Mutations in P53 cell lines confer sensitisation to P. Resistance to P due to PgP and/or alterations in the expression or structure of ^-tubulin.

Class of spindle poison Useful indications (mechanism of action)

Drug administration (IV doses in mg/m2)

Main toxicities

Pharmacokinetics and Comments of clinical metabolism interest

Docetaxel (D) (microtubule stabilizer)

Breast cancer, lung cancer (other tumours) Reproducible anti-tumour activity (response rate 35-50%) in anthracycline-resistant breast cancer stimulated further clinical development.

100 (1 h) q 3 w, Neutropenia, Metabolized in the liver Steroid pre-medication

75 q 3 w (if elevated retention reduces and delays FRS.

liver function tests). syndrome (FRS) Tau and ^4-tubulin

Weekly schedule is expression correlate with D

under investigation. sensitivity in adenocarcinoma models.

Estramustine phosphate (EP) (binds to the microtubule-associated proteins to promote microtubule disassembly)

Prostate cancer

560 mg x 2/d orally (with meal)

Gastrointestinal

75% of oral EP is absorbed. Terminal half-life: 20-40 h

Most responses observed in prostate cancer were subjective (objective response rate ~ 10%). EP has been combined with other antimicrotubules (P, VBL) and etoposide with a clinical benefit in 30-60% of patients. Overexpression of beta (III & IVa)-tubulin and Tau may play a role in resistance to EP.

which often results in resistance which is really very substantial with concentration variants in excess of 40-100-fold sometimes required to overcome such resistance. It is unclear whether this laboratory-derived resistance correlates with the types of clinical resistance which are outlined above.

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