titanocene and Neoplasms

Background Platinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients' responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity. Conclusions Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

Topics: Antineoplastic Agents; Cisplatin; DNA Adducts; DNA Repair; DNA, Neoplasm; Drug Hypersensitivity; Drug Resistance, Neoplasm; Gold Compounds; Humans; Neoplasms; Organometallic Compounds; Palladium; Platinum Compounds; Polymorphism, Genetic; Ruthenium

From the carbolithiation of 6-bis-N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl(4) resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC(50)-values obtained were of 240, and 270 microM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC(50)-value of 36 microM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC(50) = 5.5 microM) and almost ten times less cytotoxic than cisplatin, which showed an IC(50)-value of 3.3 microM, when tested on the LLC-PK cell line.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cyclopentanes; Drug Evaluation, Preclinical; Heterocyclic Compounds; Humans; Inhibitory Concentration 50; Molecular Conformation; Molecular Structure; Neoplasms; Organometallic Compounds