Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued)
Non-Classical Agents (Nitrogen Mustard Compound):
Some agents are classified as Nonclassic Alkylating Agents.4
These include bendamustine (Treanda, Bendeka) procarbazine (Matulane) and dacarbazine (DTIC).
Bendamustine is a bifunctional alkylating drug.4
Bendamustine was first synthesized in 1963 but only more recently has had its contribution to the management of hematologic cancers affirmed by clinical trials.2
Bendamustine is related to the agent chlorambucil (N-methylbenzimidazole analog).2
The substitution of the "purine-like" aromatic ring was added to provide an antimetabolite mechanism in addition to DNA alkylation.
DNA damage secondary to bendamustine exposure appears both more extensive and less likely to be repaired compared to damage caused by other alkylating drugs.
Furthermore, bendamustine appears unique in its ability to stimulate P21 and p53-induced apoptosis, S-phase cell cycle arrest and "mitotic catastrophe."2
Bendamustine administration, while causing DNA intra-and interstrand cross-links, tends to induce more DNA double-strand breaks at equitoxic doses compared to other alkylating drugs.7
Bendamustine also causes a concentration-dependent apoptosis, using changes in Bcl-2 and Bax expression profiles as indicators (in chronic B-cell lymphocytic leukemia).
DNA damage associated with bendamustine is repaired using a base-excision repair mechanism.7
This mechanism may be a basis for the lack of or limited cross-resistance exhibited by bendamustine compared to other alkylating drugs.7
Bendamustine forms cross-links with DNA, inducing inhibition of DNA synthesis and function by means of causing single-and double-stranded breaks.4
Other mechanisms that contribute to its anticancer effects include mitotic checkpoint inhibition and induction of "mitotic catastrophe."
Only partial cross-resistance between bendamustine another alkylating drugs has been noted; this finding may explain bendamustine clinical effects even in the presence of resistance development to other alkylating drugs.4
Absorption, Distribution, Metabolism, Excretion:
Following administration, bendamustine is degraded both by sulfhydryl interaction and by adduct formation with macromolecules.1
Only about 5% of parent compound is excreted in the urine.
Mean steady-state volume of distribution (Vss) is about 20-25L.5
Drug clearance is about 700 mL/min.5
Metabolites resulting from N-demethylation and oxidation exhibit antitumor activity, although metabolite activity tends to be less than that observed the parent compound.
Metabolism appears to involve the cytochrome P450 isoform, CYP1A2.2
Bendamustine plasma half-life is about 30 min.
With respect to toxicity, bendamustine exhibits a toxicity profile comparable to those of other alkylating agents.
Notably, toxicity includes a rapidly reversible myelosuppression and mucositis.1
Reactions to drug infusion may be reduced by pretreatment with corticosteroids and antihistamines.2
Drug infusion reactions have been described as an important factor for drug discontinuation.2
Some Clinical Uses:
Bendamustine has been approved for treating non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL).1
Bendamustine has also been used in treatment of Hodgkin's lymphoma, breast cancer and multiple myeloma.4
In the case of CLL, bendamustine was approved for treating patients in 2008.5
At that time a phase III clinical trial noted superior bendamustine efficacy compared to chlorambucil, using response rate in progression free survival (PFS) as endpoints.
In this setting, bendamustine appeared better tolerated compared to fludarabine yet resulted in significant myelosuppression which, particularly in elderly and infirmed patients, required a reduction in dosage.
This agent is relatively well tolerated in patients with impaired renal function given that drug excretion occurs mainly through feces.5
When considering patients with indolent non-Hodgkin lymphoma who show drug refractory disease, bendamustine exhibits particular effectiveness.7
Combination treatment in which bendamustine is administered along with rituximab resulted in response rates of about 90% with complete remission in about 57% in follicular mantle cell lymphoma.
Bendamustine can be administered both as monotherapy and in combination with other agents including etoposide, fludarabine, mitoxantrone, methotrexate, prednisone, rituximab and vincristine.7
With respect to lymphomas, based on a multicenter phase II trial, an overall response rate of about 90% was reported (35% complete remission; 54% partial response).
For previously treated patients, the response rate was about 75%.
Estimated median progression-free survival was about 19 months.
Bendamustine (Treanda) in combination with mitoxantrone and rituximab point may be a standard of care for indolent lymphoma.7
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