Cisplatin is an inorganic platinum agent (cis-diamminedichloroplatinum or cis-DDP) with anti-neoplastic activity, which forms highly reactive, charged, platinum complexes which bind to nucleophilic groups such as GC-rich sites in DNA, inducing intrastrand and interstrand DNA cross-links, as well as DNA-protein cross-links. These cross-links result in apoptosis and cell growth inhibition.
Formation of any platinated coordination complex with DNA is not sufficient for cytotoxic (that is, cell-killing) activity. The corresponding trans isomer of cisplatin (namely, trans-DDP) also forms a coordination complex with DNA but unlike cisplatin, trans-DDP is not an effective chemotherapeutic agent.
Cisplatin has been shown effective against lung cancer, testicular cancers, ovarian carcinomas, various head and neck cancers, and patients with lymphomas. However, better drugs are always desired that have greater potency and less toxicity. Moreover, there are certain types of cancer against which cisplatin is not effective.
Previously, health care workers have used cisplatin in combination therapies to treat cancer. However, despite the hope that the drugs will work together, producing a synergistic, or at least an additive effect, to cure the cancer has proved elusive. Moreover, not only has combination therapy with cisplatin failed to show additive effects, there often have been other deleterious side effects caused by the combination therapy. Even if the side effects present in combination therapy are minimized, the costs often times prove to be prohibitive.
Some combination therapies have proved to be somewhat effective against certain types of cancers. An example that has been used is the combination of cisplatin with 5-fluorouracil to treat terminally ill colon carcinoma patients. In one study, the tumors in three of nine patients decreased in size by more than 50% for varying lengths of time. However, cisplatin alone showed no effect on colon cancers in phase I clinical trials.
Resistance to platinum drugs, perhaps the most serious drawback, is multifactorial in nature, which complicates the design of compounds able to circumvent the underlying resistance mechanisms. While certain tumors tend to acquire resistance after treatment with platinum, other forms of the disease are inherently chemoresistant. Non-small cell lung cancer (NSCLC), for instance, a major cause of cancer-related mortality worldwide, is notoriously insensitive to treatment with classical cytotoxic agents, including the first generation of platinum-based drugs. Despite the poor clinical prognosis of the disease, dual-agent regimens containing cisplatin (or less toxic carboplatin) in combination with a non-platinum agent are currently the only treatment options for patients with advanced NSCLC. This sobering fact demonstrates the urgent need for novel chemotypes to combat this aggressive form of cancer.
Cellular Uptake of Cisplatin
Cisplatin generally is administered to cancer patients intravenously as a sterile sodium chloride saline solution. Once cisplatin is in the bloodstream, it is believed that cisplatin remains intact due the relatively high concentration of chloride ions (˜100 mM). The neutral compound is thought to enter the cell either by passive diffusion or active uptake. Inside the cell, the neutral cisplatin molecule undergoes hydrolysis, in which a chlorine ligand is replaced by a molecule of water, generating a positively charged species. Hydrolysis occurs inside the cell because the concentration of chloride ion is much lower, in the range of ˜3-20 mM.
The following reactions are the postulated mechanism for the process that occurs in the cell:[PtII(NH3)2Cl2]+H2O->[PtII(NH3)2Cl(H2O)]++Cl−[PtII(NH3)2Cl(H2O)]++H2O->[PtII(NH3)2(H2O)2]2++Cl−
Cisplatin is thought to coordinate with DNA mainly through the N7 nitrogen on purine bases. Generally; these nitrogen atoms (specifically, the N7 atoms of purines) are free to coordinate to cisplatin because they do not form hydrogen bonds with any other DNA bases.
Many types of cisplatin-DNA coordination complexes, or adducts, can be formed. The most important of these appear to be the ones in which the two chlorine ligands of cisplatin are replaced by purine nitrogen atoms on adjacent bases on the same strand of DNA; these complexes are referred to as 1,2-intrastrand adducts. The purine bases most commonly involved in these adducts are guanines; however, adducts involving one guanine and one adenine are also believed to occur. Generally, the formation of these adducts causes the purines to become destacked and the DNA helix to become kinked.
It is postulated that binding affects both replication and transcription of DNA, as well as mechanisms of DNA repair. The effects of both cisplatin and trans platinum on DNA replication have been studied both in vitro (using cell extracts outside the host organism) and in vivo (inside the host organism). The mechanism is believed to invoke 1,2-intrastrand adducts between cisplatin and DNA, which stops all polymerases from processing (e.g., replicating and transcribing) DNA.
In order to overcome the problem of tumor resistance to known platinum compounds, other platinum compounds need to be developed that damage DNA radically differently than the classical cross-linkers. Novel types of cytotoxic lesions may evade the cellular DNA repair machinery and/or trigger cancer cell death by alternate mechanisms at the genomic level.
Unlike the clinical cross-linking agents, it would be desirable to develop compounds that damage DNA by a dual mechanism involving monofunctional platinum binding to guanine or adenine, and intercalation of certain moieties on compounds into the base pair step adjacent to the site of platination. Accordingly, it would also be desirable to develop compounds that do not mimic the action of cisplatin.
It would be desirable to develop compounds that show a strong cytotoxic effect in a broad range of solid tumors in vitro similar, or superior, to that of the presently available clinical drugs. It would be desirable to develop compounds that prove effective against NSCLC cell lines of different genetic backgrounds. Modifications can be made to the linker geometry, the spectator ligands on the metal center, and/or intercalating portions of the molecule.
The present invention discloses the groundbreaking discovery of alternative platinum based compounds that have a dramatic effect on the treatment of various types of cancer by employing unique biocoordination chemistry leading to heretofore unseen biological activity. Moreover, the newly designed compounds of the present invention are the first examples of hybrid agents that are able to slow progression of an inherently resistant form of cancer in vivo.