Metallothionein in carcinogenesis and cancer chemotherapy.
1. Despite considerable progress, cancer continues to remain the number one health threat to human beings. Currently, the targeted antineoplastic therapy is based on an understanding of the molecular mechanisms that govern the normal proliferation and functioning of the cellular elements. Furthermore, the gene-directed therapies and antibody-based approaches are also based on modulating specific signalling processes influencing growth factors and oncogenes that alter cellular proliferation. 2. The intracellular level of metallothionein, a low molecular weight metal binding protein consisting of 25-30% cysteine, containing no aromatic amino acids or disulfide bonds and binding between 5 and 7 g atoms of group II B heavy metals per mole protein, may play an important role in regulating cellular responsiveness to DNA interactive antineoplastic agents. For example, cells with acquired resistance to cisplatin or chlorambucil overexpress metallothionein, which tends to bind these alkylating agents to a higher extent than the non-resistant cells. Since humans synthesize several isoforms of metallothionein. It is not certain which isoforms are increased in cells with acquired resistance to anti-cancer drugs. In addition to sequestering electrophilic anti-cancer drugs, metallothionein, by regulating the activities of zinc-requiring metalloenzymes or scavenging radical species, may alter the therapeutic efficacy of antineoplastic agents.
Ebadi
M
M
Department of Pharmacology, University of Nebraska Medical Center, Omaha 68198-6260.
Iversen
P L
PL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015316:Genetic Therapy; D006801:Humans; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D009841:Oligonucleotides / Q000494:pharmacology
D000970:Antineoplastic Agents; D009841:Oligonucleotides; D008668:Metallothionein