Andrea Tieghi
Denis Longo
Stefano Cozza
PLATINUM COMPOUNDS AS ANTICANCER DRUGS
PLATINUM DERIVATIVES
The cytotoxic potential of the platinum coordination complexes was recognized for first time in the sixties by Rosenberg, based on the observation of inhibitory effects on the growth of E.coli of an electric current applied to the culture broth through platinum electrodes.
The antibacterial activity was correctly attributed to formation of inorganic compounds containing platinum, chlorine and ammonia and was then shown, experimentally, that these complexes were also equipped with a high potential anticancer therapeutic.
It is thus developed a new class of chemotherapeutic drugs, derivatives of platinum, whose parent is the cis-diamino-dichloro-platinum (II) (cisplatin, CDDP), a complex containing a central atom of platinum to which they are linked two ammonium ions and two chlorine ions in cis position with respect to the horizontal plane of the molecule.
Were then developed other platinum complexes including the most widely used today in the clinic are the cis-diamino-1, 1 - cyclobutanedicarboxylatedplatin (II) (carboplatin, CBDCA), a compound in which the platinum atom is incorporated in a more complex molecule containing carbon, and the trans-L ( R, R) 1,2 - diaminocyclohexane-oxalate-platinum (II) (oxaliplatin), a platinum derivative characterized by the presence, as a ligand, of the core 1,2-diaminocyclohexane (DACH). In these three molecules on platinum has an oxidation state of +2, thus giving the structure a certain spatial configuration which is important for the antitumor activity of the same compound.
Structure of cisplatin, carboplatin and oxaliplatin.
They are compounds capable of forming covalent bonds with the DNA, bind all the bases, in particular the n-guanine and adenosine.
Their distinguishing features are those of creating cross-linking and distortion, two functionally acting on DNA, thereby implementing the cytostatic effect in particular in the G2 phase of the cell cycle, and proapoptotic.
Their great advantage, compared with alkylating agents, instead is to be less toxic and thus lowering the risk of iatrogenic malignancies.
Platinum is a substance was reduced glutathione in its form quadrivalent able to form two isomers: the first orientation of the cis-2nh2 and 2 cl. Who has great activity against cancer, and its hydrolysis in chloride, it releases its active form.
MECHANISM OF ACTION:
It is linked to the high electrophilicity, making it capable of binding to DNA but not only, in fact, can bind RNA and proteins with sulfhydryl groups, and unfortunately when he binds them that determine its toxic effects.
It is therefore a compound acting on the cell cycle, in a nonspecific manner, and its toxicity is still important and dose limiting.
In particular the compounds and their characteristics:
CIS PLATINUM
Cisplatin plays its cytotoxic activity by forming covalent adducts with DNA and has a mechanism of action similar to that of alkylating agents.
It's important remember that the behavior of the drug cisplatin is in part determined by substitution reactions that take place in water. In fact, in its form with two atoms chlorine, cisplatin is characterized by a low reactivity; in water, however, only one or both of the chlorine atoms are replaced by water molecules and this gives the composed of positive charges that enhance greatly the reactivity.
In plasma the concentration of chlorine (about 100mM) is high enough to prevent such a substitution reaction and to encourage, therefore, the intracellular penetration, through passive diffusion, the neutral form of the compound. In the cell, the low concentration of chlorine ions (about 4mM) allows, on the contrary, a rapid formation of highly reactive species downpours which, being loaded, tend to remain in the cell and induce their cytotoxic effects. At the intracellular level, in fact, the two electrophilic groups are those to react with nucleophiles of DNA, in particular, it binds the guanine at position n7.
They then are water-soluble compounds, but not able to pass the blood-brain barrier.
As regards its use in therapy it is necessary to associate it to an important hydration of the patient by means of saline solution possibly combined with mannitol or other diuretics to decrease the nephrotoxicity.
THERAPEUTIC INDICATIONS
Its main indications are in testicular cancer, use in 90% of cases, ovarian cancer and bladder cancer.
We also note a particular use in lung cancer and mesothelioma.
ADVERSE EFFECTS
It is a highly nephrotoxic, must therefore be taken into account the possible impairment of the renal patient treated, in addition there is strong ototoxicity, nausea and vomiting in addition to the classic typical of the antineoplastic treatment determined by release of serotonin, and finally the neurotoxicity is highlighted by the appearance of hand-foot syndrome, and hypoesthesia.
CARBOPLATIN
Efforts to find a compound that showed a lower toxicity than cisplatin, maintaining the antitumor efficacy, leads to the development of carboplatin, a planar complex of coordination of the Pt (II) of second generation, that presents the group of ciclobutandicarbossilate instead of the two chlorine atoms of cisplatin.
The mechanism of action of carboplatin is comparable to action of cisplatin, but it is less strong, probably because it is more stable and it has a lower rate of substitution reaction in aqueous solution. This second feature is almost certainly one of the most important reaction to determinate the cytotoxicity of platin derivatives.
Also the relative amount of each type of adduct formed by the carboplatin is different from cisplatin with a prevalence of intafilament bonds of type d (GpXpG) Pt (40%) followed by ties d (GpG) Pt (30%) and links d (APG) Pt (15%); however the quantities of intrafilament adducts remains low.
As for the cisplatin, the process of the drug inactivation provides the conjugation with reduced glutathione through a reaction catalyzed by glutathione-transferasi.
The elimination of carboplatin is done exclusively through the kidney filtration; for this reason, also this time, is necessary to modulate the dose of the drug based on the patient's renal function; this feature is estimate through the renal clearance of creatinine.
THERAPEUTIC INDICATIONS
The main indications are found in use as an antitumor fof ovary cancer, and also in combination with paclitaxel for non-small cell (NSCLC) lung cancer.
ADVERSE EFFECTS
Adverse effects are certainly lower than cis-platinum, however nausea and vomit persist but less severe. Neurotoxicity has seen with hands and feet parenthesis and we could see myelosuppression.
OXALIPLATIN
Oxaliplatin is a coordination complex of Pt (II) of the third generation and is the first of the compounds with the core of 1,2-diaminocyclohexane (DACH) to have achieved a complete clinical development. The interest for DACH complexes was born from the need to develope, modifying the functional groups, a platinum derivative that would produce a response in cisplatin / carboplatin resistant tumors.
The molecular structure of oxaliplatin has a central atom of platinum surrounded from the group DACH and a ligand represented by a bidentate oxalate. Oxaliplatin has a mechanism of action and a chemical behavior similar to the other platinum derivatives. First, the pro-drug oxaliplatin should be activated through its conversion into monochloro, dichloro and diaquo forms; this conversion has done with a non-enzymatic hydrolysis with the displacement of the oxalate group. The oxaliplatin kinetics hydrolysis is slower than cisplatin. The intermediate step, in which the DACH-Pt is bonded to two water molecules, it is very reactive and goes to react with the sulfhydryl and amino groups of proteins, and RNA DNA. The antitumor efficacy of the drug is propably due to the formation of DACH-Pt-DNA adducts. Other possible interactions include irreversible binding with biomolecules such as albumin, cysteine (Cys), methionine (Met) and reduced glutathione (GSH), specifically the conjugation with GSH, through a reaction catalyzed by the enzyme glutathione-S-transferase, represents the most significant way to inactivate the drug and to obtain cell detoxification. Then the various products of conjugation are excreted from the cell and are eliminated from body primarily by renal excretion.
INDICATIONS
The main indications are using that drug against metastatic colorectal cancer, especially in advanced stage, against non-hodgkin Lymphoma, and finally, as the previous compounds, to the ovary cancer.
ADVERSE EFFECTS
You need to remember that this compound has less adverse effects than the previous compound.
The main toxicity, occurred in 90% of patients, is neurological, consisting of an acute phase, that appears a few hours after treatment, and a chronic phase.
Neutropenia has also been demonstrated, which limits the dose to be used, in addition to the classic nausea and vomiti in correlation with the release of serotonin.
INTERACTIONS
The main interaction is with oral anticoagulants, which limit the dose can be used.
PLATINUM-BASED COMPOUNDS IN THE TREATMENT OF METASTATIC BREAST CANCER.
According to a recent publication platinum-based compounds seem to play an important role in the treatment of metastatic breast cancer.
Besides surgical treatment and radiotherapy, chemotherapy plays an central role in the treatment of breast cancer. Platinum-based compounds are widely used in today’s anticancer therapy based on their ability to covalently bind to DNA. Cisplatin and carbonplatin are successfully administered in the treatment of epithelial malignancies such as lung, head and neck, ovarian, bladder and testicular cancer. Oxaplatin is active against many cisplatin-resistant tumors such as the widespread entity colorectal cancer. Today, in the context of critical patient selection and in combination with the right partner, PBCs can be valuable agents for breast cancer therapy.
As single agents, the positive role of PBCs seem to limited to the first-line treatment setting. In previously untreated patients with MBC, high RRs were observed. In previously treated patients, the RRs were lower than those reported for first-line treatment.
Combinations of PBCs and other agents have been extensively explored and showed better results than single-agent therapy, especially in pretreated patients. Regimens containing cisplatin/carboplatin together with taxanes showed the highest RRs. PBCs administered simultaneously with the vinca alkaloid vinorelbine were also active and well tolerated in anthracycline and taxane pretreated patients. PBCs together with nucleoside analogues were found to have low to moderate activity. The combination of cisplatin with etoposide showed moderate activity but elevate toxicity. Unlike with other agents, the combination of cisplatin with etoposide showed higher RRs when used as first-line therapy compared to studies in previously treated patients. The overall results for the combination of PBCs with antracyclines were disappointing, and these combinations were not suggested. The activities were limited and the toxicities were elevated.
The use of PBCs against MBC seems to be a reasonable therapeutic option in the context of critical patient selection and/or in combination with other appropriate anticancer drugs.
CONCLUSIONS
The biochemistry and molecular biology study through based on the research of the DNA molecule have made possible the discovery of important drugs that interacting with it are able to block the mechanisms at the base of carcinogenesis, evolution and progression of many types of carcinomas not otherwise treatable.
In particular, the platinum compounds, classic antineoplastic drugs, and wide clinical use, have represented a significant improvement in the prognosis and survival in particular cancers such as colorectal, ovarian and lung cancer
Platinum-based compounds for the treatment of metastatic breast cancer. Chemotherapy 2011
