Future Prospects for Old Chemotherapeutic Drugs in the Target-Specific Era; Pharmaceutics, Combinations, Co-Drugs and Prodrugs with Melphalan as an Example

Abstract

During the last decade, resulting from expanded knowledge in tumor biology, several new and target-specific approaches have been presented. With some exceptions, however, most early clinical trials with these compounds are discouraging, suggesting that the expanding knowledge might not easily translate into new substantially better anti-cancer drugs. One of the classical chemotherapeutic agents is melphalan, first synthesized over fifty years ago. The anti-tumor effect has been attributed to alkylation of cellular nucleophiles, among them DNA. Intravenous melphalan has single-agent activity in a variety of solid tumors and has good activity alone or combined with other drugs or radiation in high-dose bone marrow transplant regimens for breast cancer, ovarian cancer, testicular cancer and multiple myeloma. Recent studies suggest a continuous role for melphalan as part of high dose combination therapy in advanced solid tumor malignancies. Immediately after the first publication on melphalan (p-L-bis(2-chloroethyl)aminophenylalanine), investigators began attempting to improve the therapeutic index and thus provide a greater margin of clinical safety during treatment with the drug. The amino-acid based chemical structure of melphalan invites to modification of both the N-and C-termini as well as incorporation into peptides.In this review we discuss the past and present history of melphalan in the perspective of modern cancer chemotherapy, from the medicinal chemist's point of view, and with special emphasis on how target-directed approaches have been applied to the molecule.

smProdrugs: A repository of small molecule prodrugs

“…Such drugs are called co-drugs and upon activation release two active drugs in the body. (Lau et al, 2008) (Wickstrom et al, 2006) Some bioprecursor prodrugs do not contain a promoiety, but obtained through modification (such as oxidation or reduction) of the active drug itself. This modified prodrug is metabolically transformed back to the active drug.…”

Melflufen - a peptidase-potentiated alkylating agent in clinical trials

“…The drug has now been replaced by modern chemotherapeutics in most diagnoses, and currently melphalan treatment is in most countries limited to multiple myeloma and as a component of high-dose myeloablative regimens. The amino acid-based chemical structure of melphalan provides possibilities for modification of the N - and C -termini and incorporation into peptides, targeting its cytotoxicity to cells with peptide receptors and/or enzymatic activating systems (reviewed in [ 15 ]). One such derivative is melphalan flufenamide (L-melphalanyl-p-L-fluorophenylalanine ethyl ester hydrochloride), abbreviated melflufen and previously denoted J1 (Figure 1 ).…”