Though cis-platin is highly effective, its counterpart trans-platin is counterintuitively not (7). Trans-platin is highly reactive with the environments that lead to reaching the DNA, and this reactivity results in the totality of the administered compound becoming deactivated prior to reacting with the DNA (9).
Also the DNA lesion caused by cis-platin on the 1,2 intrastrand crosslinks between adjacent purines is an act that trans-platin cannot do when looking from a stereochemical perspective (9). Recently, by adding bulky ligands in replacement of the two amines on trans-platin, antitumor activity has been found, and even activity on cis-platin resistant tumors, suggesting that anticancer mechanism is not limited to lesion causing 1,2 intrastrand crosslinks between adjacent purines (9).
Due to the complexity of the interactions cis-platin and trans-platin undergo in the body, and the specific interactions the compounds undergo in presence of different tumors and different mutations to pathways, we have yet to determine the exact mechanisms at play that cause cell repair, apoptosis, intrinsic resistance to cis-platin, and acquired resistance to cisplatin alongside the mechanisms of trans-platin and its recently recognized success in causing apoptosis (9).
Cis-platin’s widespread capabilities deemed it the title “drug of the 20th century”, but clinical findings quickly revealed cisplatin’s toxicity and problems regarding specific cancer resistance to the drug (7). Cis-platin’s toxcicity is a result of ironically its ability to halt tumor production and eradicate its presence (5). This ability comes from cis-platin reactivity with DNA in general, not just that of mutated cells (5). This non-specific reactivity causes the same events that lead to apoptotic activity in all cells affected by he drug, specifically it inhibits DNA replication and thus cell division and it inhibits mRNA production and thus the production of essential proteins is also suppressed (5). Cisplatin’s toxicity is also tied to its reactivity to proteins as it travels through the bloodstream and through the cell prior to reacting with the DNA, an estimate of this process states that upwards of 98% of the administered drug becomes deactivated by binding and the products of this process can in many cases cause further toxic damage to the body (7).
The result of cisplatin’s toxicity can induce serious side effects such as nephrotoxicity, neurotoxicity, ototoxicity, nausea, and vomiting (7). Clinical findings have shown the intrinsic resistance some tumors represent in the presence of cis-platin and the acquired resistance some tumors develop during cis-platin chemotherapy(10). The specific reasons for the intrinsic resistance some tumors represent is very tumor and mutation type specific, it is also not well understood (10).
Acquisition of resistance to cis-platin is also due to a multitude of reasons including: decreased diffusion or active transport of cisplatin into the cell, increased efflux of platinum from the cell, increased levels of cytoplasmic detoxification caused by increases in proteins such as thiols, and/or the increased repair or tolerance of the distortion caused by DNA-platinum adducts (3). Both the limiting nature and potential cisplatin promised has caused a surge in platinum based chemotherapeutic agent research.
With over 3000 cisplatin analogues synthesized, and of which 28 of being selected for clinical trials, only a select few have yielded any clinical advantage over cisplatin (6). For a new chemotherapeutic agent to gain clinical approval, it must surpass the benchmark cisplatin has set, the new potential drug must have one of the following advantages: specific cancers are not naturally resistant or able to become resistant to the drug, it is less toxic, or it is able to be orally administered rather than intravenously (7).
To better understand cisplatin, the mechanisms of chemotherapeutic agents, the hard-soft acid-base principle, the stability and mechanisms of isomers, and the interaction between inorganic and biochemistry, both cis and trans-platin where produced in the lab. To gain an in-depth understanding of the mechanisms involved in the production of the two isomers, unlabeled protocols where randomly assigned and the production of either isomer was only indicated by the concluding thiourea test.
The concluding reason for the lab was to identify the production of either isomer by a chemical test on the product of the protocol in comparison to known samples of both isomers. Experimental The protocol assigned resulted in a two day experiment with a seven day gap between the two experimentation days. The following paragraph describes the procedures and steps taken on day one of the experiment, which focused entirely on the synthesis of the isomer based on Protocol B. Certain chemical agents used on day one have both health and safety risks, specific details regarding these risks will be explained in more detail in the following procedures, but if unfamiliar with any of these materials it is essential to thoroughly review the safety data sheets of the chemical manufacturers in question.
Also all procedures should be done with the use of non-latex laboratory gloves and protective eyewear in a fume hood environment. To a 50ml beaker, 0. 268g of potassium tetrachlorplatinate (hazardous), 12. ml of deionized water, and a stir bar are added creating a red solution. To this 20 drops from a Pasteur pipette of 2 molar hydrochloric acid (corrosive) is dropped into the beaker. The solution, with the aid of the stir bar above a magnetic hot plate, turns orange. Simultaneously, another hot plate is being heated, upon which the solution is placed, quickly heating it to 880C. While maintaining solution temperature and vigorously using a stir bar, 6. 1ml of 2 molar ammonium hydroxide are added to the solution, turning the orange solution to a very pale yellow.
The heating procedure continues at 880C, being careful as to not overheat the solution past 900C to avoid unintended chemical decomposition, resulting in a solution volume of approximately 14ml. The heating of the solution, and the evolution of gas, also turns the solution clear. To the reduced volume, 30. 1ml of 6 molar hydrochloric acid (corrosive) is added while stirring and maintaining solution temperature at 880C. The heating of the solution continues to lower its ve and as this occurs a cloudy precipitate begins to accumulate in the solution while turning a pale yellow.
It is important to note that while heating the solution, the total volume should never drop below 10ml in order to yield any significant product. After the formation of the precipitate, the solution is placed in an ice water bath. Following the cooling of the solution for approximately 15 minutes, a 4ml frit is used to filter the accumulated precipitate out of solution. The product is then washed with a few drops cold ethanol (flammable) and diethyl ether (flammable).
The product produced is a light yellow powder (irritant) which is stored in a cool dry climate for passive evaporation. Day two of the experiment begins the seventh day following the conclusion of day one’s procedures, and focuses on the massing of the product from day one and on the chemical characterization of the product. All notes regarding safety presented in the previous paragraph hold true for day two as well. The product created on day one is scraped from the frit and massed using an electronic scale capable of measuring to the thousandth decimal place of the gram.
The massing procedure yielded 9 milligrams of product. All of the massed product was then added to a test tube along with a few drops of deionized water, and then the occluded test tube was shaken vigorously in an attempt to dissolve the product. Two other test tubes where also identically prepared with known compounds of cis and transplatin, 21mg and 35mg respectively. All three test tubes where placed in warm mineral oil baths, and a few drops of thiourea (potential carcinogen) where added to each of the test tubes. Results
The thiourea tests done on day two of the experimental section yielded results that indicated the isomer created by our assigned Protocol B. When thiourea was added to the known cisplatin sample it turned from a light orange solution to a brighter orange solution, when the same procedure was done with the known light yellow transplatin solution no color change was found. The thiourea test with the sample created was almost identical to that of the known transplatin’s test, where the pale yellow solution of product did not change in color in the presence of thiourea.
The results of this qualitative characterization process causes the conclusion that transplatin was produced by our protocol. The results hence show the formation of the nonchemotherapeutic active agent, transplatin. The hands on synthesis of this isomer may not have succeeded in directly answering any of the problems associated with the search for new chemotherapeutic agents, but the understanding gained by me and all of my fellow scientists in synthesizing and characterizing the isomers will act as a base of knowledge upon which one day we will collectively create a more effective drug.