Platinum, diamminedichloro-

298.03 g/mol

296.939948 g/mol

247-419-7

241517|131558

Deep yellow solid|Yellow crystals|White powder|Orange-yellow crystals

L01XA01

2 Ų

1.59590

3.738 g/cu m

270 °C (decomposes)|270°C

Insol in most common solvents except dimethyl formamide|Soluble 1 (part) in 42 (parts) of dimethylprimanide|In water, 2.53X10+3 mg/l @ 25 °C

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/|/Store/ at room temp (27 °C) & protect from light; it should not be refrigerated.|It is recommended that the constituted soln not be refrigerated because of the formation of a crystalline precipitate. ... If the soln is frozen, it should be thawed at room temp until the precipitate dissolves. The manufacturer states that this thawing will not adversely affect the chemical or physical stability of the product.

Slowly changes to trans-form in aqueous solution; decomposes @ 270 °C|Tb3+, a fluorescent probe which fluoresces primarily with guanine and xanthine bases, was used to investigate the interaction of platinum complexes with DNA and RNA. Cis-dichlorodiammineplatinum(II), a potent antitumor agent, produced a marked enhancement in fluorescence intensity when reacted with double-stranded DNA. The inactive isomer, trans-dichlorodiammineplatinum produced no change in Tb3+ fluorescence.|The trans-isomer disrupts the DNA structure more rapidly /than cis-platin/ as shown by the large incr of intensity of the characteristic thymine bands at 1238 and 1662 cm. The study confirms the fact that cis-platin and its inactive trans-isomer are covalently bound to the N7-guanine sites but the perturbation is different in the two cases.

SLOWLY CHANGES TO TRANS-FORM IN AQ SOLN|Intact vials of the dry product are stable for 2 yr from manufacture when stored at room temp (27 °C) & protected from light; it should not be refrigerated. ... The manufacturer states that cisplatin is stable for 20 hr after constitution when stored at 27 °C. Constitution with bacteriostatic water for injection, containing benzyl alcohol or parabens, to a concn of 1 mg/ml results in solns that are reported to be stable for at least 72 hr at 25 °C. After initial vial entry, the aqueous cisplatin injection in amber vials is stable for 28 days if it is protected from light or for 7 days if it is exposed to fluorescent room light.|The pH of maximum stability is 3.5-5.5. Alkaline media should be avoided because of increased hydrolysis.|The stability of cisplatin in soln is dependent on the chloride ion concn present. In solns with an inadequate chloride content, one or both chloride ions in the cisplatin molecule are displaced by water, forming mono- & di-aquo species. The minimum acceptable chloride ion concn is about 0.040 mol/L, the equivalent of about 0.2% sodium chloride.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/|For more Disposal Methods (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (6 total), please visit the HSDB record page.

Cisplatin ... is incompatible in solns having a low chloride content. ... Cisplatin may react with sodium thiosulfate, sodium metabisulfite, & sodium bisulfite in soln, rapidly & completely inactivating the cisplatin.|Because of an interaction occurring between cisplatin & the metal aluminum, only admin equipment such as needles, syringes, catheters, & sets that contain no aluminum should be used for this drug. Aluminum in contact with cisplatin soln will result in a replacement oxidation-reduction reaction, forcing platinum from the cisplatin molecule out of soln & appearing as a black or brown precipitate.

Moroso MJ, Blair RL; A Review of Cis-platinum Ototoxicity. J Otolaryngol 12 (6): 365-9 (1983). The review discusses chemically-induced hearing loss.|National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Cisplatin (15663-27-1) is listed as reasonably anticipated to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s047cisp.pdf]|WHO; Environmental Health Criteria 119: Principles and Methods for the Assessment of Nephrotoxicity Associated with Exposure to Chemicals (1991)

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/|Employees should be provided with and required to use impervious clothing, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with soluble platinum salts or liquids containing soluble platinum salts, where skin contact may occur. ... Employees should be provided with and required to use dust- and splash-proof safety goggles where soluble platinum salts or liquids containing soluble platinum salts may contact the eyes. /Soluble platinum salts/|Recommendations for respirator selection. Max. concn for use: 4 mg/cu m. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. /Platinum (soluble salts as Pt)/|Recommendations for respirator selection. Max. concn for use: 0.1 mg/cu m. Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter.; Any self-contained breathing apparatus with a full facepiece.; Any supplied-air respirator with a full facepiece. /Platinum (soluble salts as Pt)/|For more Personal Protective Equipment (PPE) (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (7 total), please visit the HSDB record page.

In fire fighting, the minimum respiratory protection required above 0.002 mg/cu m is a self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode. /Soluble platinum salts/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/|Persons not wearing protective equipment and clothing should be restricted from areas of spills until cleanup has been completed. If soluble platinum salts or liquids containing soluble salts are spilled, the following steps should be taken: 1. Ventilate area of spill; 2. Collect spilled material in the most convenient and safe manner for reclamation or for disposal in a secured sanitary landfill. Liquids containing soluble platinum salts should be absorbed in vermiculite, dry sand, earth, or a similar material, /Soluble platinum salts/

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/|For more Preventive Measures (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (18 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/|PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

... Corrosive to skin ... .|The dusts of soluble platinum salts cause a burning sensation in the eyes, lacrimation, and conjunctival hyperemia, sometimes associated with photophobia, which suggests that the corneal epithelium may be involved. /Soluble platinum salts/|Inhalation of the dust of sol platinum salts is irritating. /Platinum/

IDENTIFICATION: Cisplatin is an antineoplastic cytostatic drug. Cisplain is deep yellow solid. Soluble in water, and in sodium chloride solution. Slowly changes from the cis to the trans form in aqueous solution. Soluble in dimethylformamide. Insoluble in most common solvents. Indications: Cisplatin is indicated for the following conditions: Single agent for the treatment of transitional cell bladder carcinoma that is no longer amenable to local treatment such as surgery and/or radiation therapy. Locally advanced or metastatic transitional cell carcinoma involving the renal pelvis, ureter, bladder and/or urethra. In combination with radiation treatment to treat bilharzial bladder cancer and together with doxorubicin and cyclophosphamide to treat locally advanced bladder cancer. The palliative treatment of recurrent or metastatic squamous cell carcinomas of the head or neck. Treatment of lung cancer, principally as a component of various chemotherapeutic regimens in the treatment of non-small cell lung carcinomas. It is often combined with other agents such as etoposide, vinblastine or vindesine to obtain a better response rate in lung cancer. Its use alone has some value but in combination the results are more noticeable in the palliative treatment of recurrent or advanced squamous cell carcinoma of the cervix and metastatic testicular carcinoma. Other types of carcinomas in which cisplatin has been tried included the following: osteogenic sarcoma, neuroblastoma and recurrent brain tumors in children, advanced esophageal carcinoma and advanced prostatic carcinoma. In combination with agents such as bleomycin, methotrexate, vincristine or vinblastine, fluorouracil in various regimes (all together or singularly depending on the protocol and the carcinoma type). Combinations of these agents have been reported to have a better response rate than if cisplatin were used alone. HUMAN EXPOSURE: Summary: Main Risks and Target Organs: The main risks experienced during cisplatin therapy and overdosage include nephrotoxicity, electrolyte disturbances, myelosuppression, neurotoxicity, anaphylactic reactions and ototoxicity. Nausea and vomiting can be severe. Rarer risks include cardiovascular effects, ocular effects, and hepatic effects. Most effects of overdosage are not usually seen immediately, but occur several days to months after the event. The causes of death from an overdose from cisplatin include myelosuppression, renal failure and tetany. Summary of Clinical Effects: Renal toxicity is cumulative and seen usually after several courses of cisplatin or after overdose. Disturbances in electrolytes can be a long term manifestation due to the cisplatin induced renal tubular dysfunction. Hypomagnesemia, hypocalcemia and hypokalemia are commonly seen in cisplatin induced renal toxicity and can persist for months after termination of therapy. Hematological effects of cisplatin (myelosuppression and anemia) are cumulative and in overdosage the hematopoietic system must be supported to prevent complications of infection. Cisplatin induces marked nausea and vomiting in almost all patients. Anaphylactoid reactions have occurred during normal therapy with cisplatin and must be treated vigorously. Cisplatin causes electrolyte disturbances which are a direct result of cisplatin induced renal tubular dysfunction. Cisplatin causes marked excretion of calcium, magnesium and potassium and to a lesser extent zinc, copper and amino acids. These disturbances must be corrected to prevent complications. Clinical features: Renal toxicity is manifested by an increase in serum creatinine, BUN, serum uric acid and/or a decrease in creatinine clearance and glomerular filtration rate. The renal impairment is a direct result of cisplatin induced renal tubular damage leading ultimately to renal failure. Disturbances have been seen in serum electrolytes due principally to cisplatin induced renal tubular dysfunction. Patients subsequently develop Hypomagnesemia, hypocalcemia and hypokalemia and to a lesser extent hypophosphatemia and hyponatremia. Cisplatin produces marked nausea and vomiting in almost all patients to the extent that some patients experience anticipatory nausea and vomiting. Diarrhea has also occurred but with less frequency than nausea and vomiting. Ototoxicity develops in various degrees on cisplatin therapy. In larger and prolonged dosing with cisplatin the ototoxicity can be irreversible. Myelosuppression is a common problem seen as leucopenia, thrombocytopenia and anemia and if severe enough can cause the death of the patient. Myelosuppression can be cumulative. Anaphylactoid reactions can occur when cisplatin is given. Cardiovascular effects are rare but include bradycardia, left bundle branch block and congestive heart failure. Hepatic enzyme activities in the sera become elevated including AST (SGOT) and ALT (SGPT). Precautions: Extreme care should be taken by persons preparing and administering cisplatin and those handling the urine of treated patients. Routes of entry: Cisplatin is not effective when administered orally. Dermal: Cisplatin is not administered dermally. Avoid dermal contact and absorption during administration. Eye: Eye contamination may be a possible source of poisoning during intravenous administration of cisplatin. Parenteral: Cisplatin is only available in the injectable form. The parenteral routes, intravenous, intra-arterial and intraperitoneal, have all been used in cisplatin therapy and poisoning would most likely occur by these three routes. Absorption by route of exposure: Intravenous: Totally absorbed after intravenous use. Rapid intravenous injection of cisplatin over 1 to 5 minutes or rapid intravenous infusion over 15 minutes or one hour, results in peak plasma concentrations immediately. When cisplatin is administered by intravenous infusion over 6 to 24 hours the plasma concentrations of total platinum increase gradually during the infusion and reach peak concentrations immediately following the end of the infusions. When mannitol is given at the same time as cisplatin, the peak plasma concentrations of non protein-bound platinum appears to be increased. Intra-arterial: When cisplatin is administered by intra-arterial infusion, the local tumor exposure of the drug is increased as compared with intravenous administration. Intraperitoneal: Cisplatin is rapidly and well absorbed systemically following intraperitoneal administration. This route gives 50 to 100% plasma concentration in comparison with the intravenous route. Intraperitoneal fluid concentration of the drug is greatly increased as compared with intravenous administration. Distribution by route of exposure: Following the intravenous administration of Cisplatin, the drug is widely distributed into body fluids and tissues. The highest concentrations can be seen in the kidneys, liver and intestines, and can persist for up to 2 to 4 weeks. However, concentrations can also be found in the muscles, bladder, testes, prostate, pancreas and spleen. Cisplatin has also been found in the following tissues; small and large intestines, adrenals, heart, lungs, lymph nodes, thyroid, gall bladder, thymus, cerebrum, cerebellum, ovaries and uterus. Platinum appears to accumulate in body tissues following administration of cisplatin and has been detected in many of these tissues for up to 6 months after the last dose of the drug. Platinum also has been found in leucocytes and erythrocytes. Cisplatin and any platinum-containing products are rapidly and extensively bound to tissue and plasma proteins, including albumin, gamma-globulins and transferrin. Binding to tissue and plasma proteins appears to be essentially irreversible with the bound platinum remaining in plasma during the lifespan of the albumin molecule. Protein binding increases with time and less than 2 to 10% of platinum in blood remains unbound several hours after intravenous administration of cisplatin. The extent of protein binding is about 90% and this occurs essentially within the first two hours after a dose. Penetration into the central nervous system (CNS) does not occur readily. The resultant levels are low in the CNS, but significant amounts of cisplatin can be detected in intracerebral tumor tissue and edematous brain tissue adjacent to the tumor. In healthy brain tissue concentrations appear to be low. Metabolism: The metabolic fate of cisplatin has not been completely elucidated. There is little evidence to date that the drug undergoes enzymatic biotransformation. The cisplatin molecule has chloride ligands on it and it is believed that these are displaced by water thus forming positively charged platinum complexes that react with nucleophilic sites. Their rate and extent depends on the strength, concentration and accessibility of the nucleophiles. The chemical identities of the metabolites of cisplatin have been found but have yet to be identified. There is a strong possibility that cisplatin and its metabolites undergo enterohepatic circulation. Elimination by route of exposure: Intact cisplatin and its metabolites are excreted principally in urine. It occurs predominantly via glomerular filtration but there is some evidence that secretion and reabsorption of cisplatin and its metabolites also occurs. Initially renal clearance of total platinum equals creatinine clearance and represents elimination of non-protein bound platinum molecules including intact cisplatin. As extensive protein binding occurs then clearance declines rapidly, resulting in a prolonged excretory phase. The ultimate rate of fall of total plasma platinum concentration is governed by the rate of degradation of plasma proteins bearing bound platinum. A small amount of cisplatin is excreted via the bile and saliva. Elimination half-life of cisplatin (Adults): Normal renal function: 2 to 72 hr. End stage renal disease: 1 to 240 hr. Mode of Action: Toxicodynamics: Cisplatin appears to be cycle-phase nonspecific and will cause cell death in all cells. It is in those cells which turn over rapidly (tumor cells, skin cells, gastrointestinal cells, bone marrow cells) that cell death will occur at a faster rate than other cells with a slower turnover rate (e.g. muscle cells). Cisplatin exerts its antineoplastic activity when it has the cis-configuration and without a charge on the molecule. The trans-configuration is inactive. Pharmacodynamics: Cisplatin complex moves through cell membranes in an unionized form and this is achieved in the relatively high chloride concentration in the plasma. Intracellularly the concentration of chloride ions is lower than in the plasma and the chloride ligands on the cisplatin complex are displaced by water. The result is the formation of positively charged platinum complexes that are toxic to cells. The cisplatin molecule binds to the DNA molecule at the guanine bases and thus inhibits DNA synthesis, protein and RNA synthesis (the latter two are inhibited to a lesser degree). The drug forms intrastrand and interstrand cross links in the DNA molecule and appears to correlate well with the cytotoxicity of the drug. The tumor cells amass an overburden of mutations which lead eventually to the cell's death. Cisplatin also has immunosuppressive, radiosensitizing and antimicrobial properties. The exact mechanism of action of cisplatin is not yet understood but the drug has biochemical properties similar to those of bifunctional alkylating agents. Human Data: Adults: The major toxicity caused during cisplatin treatment is dose related and cumulative. For example, renal tubular function impairment can occur during the second week of therapy and if higher doses or repeated courses of cisplatin are given then irreversible renal damage can occur. Teratogenicity: There is positive evidence of human fetal risk, so the benefits in pregnant women must be weighed against the risk. Interactions: Nephrotoxic drugs: Cisplatin produces cumulative nephrotoxicity that can be potentiated by nephrotoxic drugs (aminoglycosides, cephalosporins and amphoteracin). Aminoglycosides: Concurrent administration of aminoglycosides within 1-2 weeks of cisplatin therapy has been associated with an increased risk of nephrotoxicity and renal failure. Therefore aminoglycosides should be used with extreme care during treatment. Cisplatin ototoxicity is enhanced with the use of loop diuretics. ANIMAL STUDIES: Cisplatin is carcinogenic in animals. Mutagenicity: Cisplatin is mutagenic in bacterial cultures and produces chromosome aberrations in animal cells in tissue cultures.

The RNA synthesis in vitro by Escherichia coli RNA polymerase were found to be highly sensitive to cis-platin inhibition. The degree of inhibition was in proportion to the length of time of template preincubation with cisplatin. It was found that adriamycin significantly enhanced the inhibitory effect of cisplatin & the total effect was greater than the sum of the effects of each drug used individually.|A549 lung cancer cells were treated simultaneously with cisplatin (0, 1.25, 2.5, and 5 ug/ml) and other cytotoxic agents. Cisplatin additively incr the cytotoxic effects of etoposide, mitomycin C, adriamycin, 5-fluorouracil and 1-beta-D-arabinofuranosylcytosine, but antagonized those of vincristine, vindesine, vinblastine and podophyllotoxin. The antagonism between cisplatin and vincristine was also observed with HT29 colon cancer cells, NC65 renal carcinoma cells and A431 epidermoid carcinoma cells when these cells were simultaneously exposed to both agents. When A549 cells were exposed to cisplatin and vincristine sequentially (6 hr incubation with each agent), the antagonism between them was evident when the cells were pretreated with cisplatin, but not when treated in the opposite sequence.|A study was conducted to investigate whether the antiemetic drug metoclopramide, a benzamide derivative (4-amino-N-2-(diethylaminoethyl)-5-chloro-2-methoxybenzamide), potentiates the effect of cis-platin on squamous cell carcinoma. Human squamous cell carcinoma of the head and neck (tumor line AB and EH) xenografted to nude mice were used. Two administration schedules were tested: (a) metoclopramide (2.0 mg/kg ip) given 1 hr before cis-platin (7.5 mg/kg ip); and (b) metoclopramide (3 x 2.0 mg/kg) given concomitant to, 24, and 48 hr after cis-platin (7.5 mg/kg) administration. Treatment efficacies were compared using the area under the growth curves, tumor vol, and specific growth delay. There was no mortality and no wt loss of significance in any treatment group. Metoclopramide alone did not induce any significant reduction in area under the growth curves tumor vol, or specific growth delay with either treatment schedule. Cis-platin alone gave a significant reduction of tumor growth in tumor line AB but not in tumor line EH. In schedule (a), the addition of metoclopramide did not give any additive effect. In schedule (b), for both tumor lines, metoclopramide enhanced the effect of cis-platin by significantly reducing the area under the growth curves (AB: p < 0.0001; EH: p < 0.001) and incr specific growth delay (AB: p < 0.012; EH: p < 0.001) when compared to the tumors given cis-platin alone.|The ability of nifedipine, a dihydropyridine class calcium channel blocker, to overcome cis-platin resistance in a murine tumor line variant B16a-platinum, developed for resistance to cis-platin, was examined. Nifedipine significantly enhanced the antitumor actions of cis-platin against primary subcutaneous B16A-platinum tumors and their spontaneous pulmonary metastases. The pharmacokinetics and dose response interactions in vivo between nifedipine and cis-platin were also characterized. The in vivo efficacy of nifedipine and other calcium active compounds including structurally similar calcium channel blockers (nimodipine, nicardipine) from the dihydropyridine class, structurally different calcium channel blockers from the benzothiazepine (diltiazem) and the phenylalkylamine (verapamil) classes, and calmodulin antagonists (trifluoperazine and calmidazolium) were examined for their ability to enhance the antitumor action of cis-platin. Nifedipine was included as the standard or reference compound. All compounds studied failed to enhance the antitumor actions of cis-platin.|For more Interactions (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (20 total), please visit the HSDB record page.

LD50 Rat oral approx 20 mg/kg|LD50 Rat oral 25,800 ug/kg|LD50 Rat ip 6400 ug/kg|LD50 Rat sc 8100 ug/kg|For more Non-Human Toxicity Values (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (15 total), please visit the HSDB record page.

cis-Diaminedichloroplatinum is not known to occur in nature(1).

cis-Diaminedichloroplatinum is produced as a medicine for treatment of a variety of malignancies(1) which could result in environmental release from its production and use(SRC).

TERRESTRIAL FATE: cis-Diaminedichloroplatinum has an aqueous solubility of 2,530 mg/l(1) and the compound is stable towards ionization(SRC). The complex should leach through soil unless it is converted into an insoluble simple salt such as platinum hydroxide or platinum monosulfide, or converted into ionic species by biotic and abiotic reactions(SRC). The infiltration of the ionic species in soil may be retarded by adsorption process(SRC).|The aqueous solubility of cis-diaminedichloroplatinum(1) suggests that upon entering water it will be present in the aqueous solution. cis-Diaminedichloroplatinum is known to slowly transform to trans-platin in water(2). Some of the trans-diaminedichloroplatinum should adsorb to suspended solids and sediments in water. The majority of the compound should stay in the aquatic phase unless biotic or abiotic process convert it into an ionic salt or insoluble precipitate(SRC). The ionic salt could be adsorbed by clay materials, ion-exchange process, and precipitate out in the sediment(SRC).|ATMOSPHERIC FATE: Based on cis-diaminedichloroplatinum's high melting point and its pattern of use(1), it is unlikely that the compound would be present in the atmosphere(SRC).

In aqueous solution, cis-diaminedichloroplatinum slowly transforms to trans-diaminedichloroplatinum(1).

cis-Diaminedichloroplatinum: Not found in milk. /from Table 6/

Since cis-diaminedichloroplatinum is packaged in powdered form in vials(1), it is likely that workers would be exposed to cis-diaminedichloroplatinum via skin absorption during production and via inhalation of the powder during preparation of dosage forms(SRC). Exposure of hospital workers to cis-diaminedichloroplatinum may occur with its use as a chemotherapy drug(SRC).

cis-Diaminedichloroplatinum was found in the concn range 1.88-3.03 microgram/ml in blood/plasma of patients injected with cis-diaminedichloroplatinum(1).

Antineoplastic Agents; Cross-Linking Reagents; Radiation-Sensitizing Agents|CISPLATIN IS USED IN HUMAN MEDICINE FOR THE TREATMENT OF A VARIETY OF MALIGNANCIES ... TESTICULAR TUMORS, MALIGNANT MELANOMA, OSTEOGENIC SARCOMA & CARCINOMAS OF THE BLADDER, LUNG (NON-SMALL-CELL), UTERINE CERVIX, OVARY & SQUAMOUS CARCINOMA OF THE HEAD & NECK REGION.|THE USUAL IV DOSE OF CISPLATIN IS 20 MG/SQ M/DAY FOR 5 DAYS OR 100 MG/SQ M, GIVEN ONCE EVERY 4 WK. DOSES AS HIGH AS 40 MG/SQ M DAILY FOR 5 DAYS HAVE BEEN USED ALONE OR TOGETHER WITH CYCLOPHOSPHAMIDE FOR THE TREATMENT OF PATIENTS WITH ADVANCED OVARIAN CANCER, BUT RESULT IN GREATER RENAL, HEARING, & NEUROLOGICAL TOXICITY. TO PREVENT RENAL TOXICITY, HYDRATION OF THE PATIENT BY THE INFUSION OF 1-2 L OF NORMAL SALINE PRIOR TO TREATMENT IS RECOMMENDED. THE APPROPRIATE AMT OF CISPLATIN IS THEN DILUTED IN A SOLN OF DEXTROSE & SALINE & ADMIN IV OVER A PERIOD OF 6-8 HR. SINCE ALUMINUM REACTS WITH AND INACTIVATES CISPLATIN, IT IS IMPORTANT NOT TO USE NEEDLES OR OTHER EQUIPMENT THAT CONTAINS ALUMINUM WHEN PREPARING OR ADMINISTERING THE DRUG.|From June 1977 to June 1987, 68 patients were treated with cisplatin for recurrent squamous cell carcinoma of the cervix as the primary chemotherapeutic agent & evaluated for response &/or survival. Patients were treated with 50-100 mg/sq m of cisplatin at 3 wk intervals. Patients with disease confined to the chest had a 53% complete response rate with an overall response rate of 73%. Patients with localized pelvic recurrence or persistence demonstrated no complete responses & a 21% overall response rate. Isolated chest metastases responded more frequently to cisplatin than pelvic recurrences (73% vs 22%, p=0.0007); however, location of recurrence did not significantly alter survival (mean 22.7 mo vs 14.1 mo; p=0.24). Concomitant disease in other locations reduced the likelihood of response in the chest (p>0.05) by virtue of lack of response in those other sites. Lesion size, clinical stage, patient age, & duration from primary treatment to recurrence were not of significance with regard to response or survival.|For more Therapeutic Uses (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (6 total), please visit the HSDB record page.

THE DRUG SHOULD NOT BE ADMINISTERED THROUGH AN ALUMINUM NEEDLE, SINCE ALUMINUM REACTS WITH AND INACTIVATES THE DRUG.|Possible inactivation of cis-platinum may occur when sodium bisulfite is added to cis-platinum in iv fluid prior to admin.|A Mallory-Weiss tear was reported in a patient as a complication of cancer chemotherapy including cis-platin. It is suggested that the Mallory-Weiss syndrome should be included in the differential diagnosis of any patient with epigastric pain, hematemesis, or melena after chemotherapy induced retching or vomiting.|The auditory function of subjects receiving cisplatin for genitourinary tumors & head & neck cancers was serially monitored with conventional audiometry & with a high frequency testing system. Results reveal a high incidence of nonreversible cochlear toxicity with a predilection for involvement of the higher frequencies. Cochlear toxicity was detected earlier with the high frequency evaluation system.|For more Drug Warnings (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (21 total), please visit the HSDB record page.

AFTER RAPID IV ADMIN /TO HUMAN PATIENTS/ ... THE DRUG HAS AN INITIAL ELIMINATION HALF-LIFE IN PLASMA OF 25-50 MIN; CONCNS OF TOTAL DRUG, BOUND & UNBOUND, FALL THEREAFTER, WITH A HALF-LIFE OF 24 HR OR LONGER. MORE THAN 90% OF THE PLATINUM IN THE BLOOD IS COVALENTLY BOUND TO PLASMA PROTEINS. HIGH CONCNS ... ARE FOUND IN THE KIDNEY, LIVER, INTESTINES, & TESTES, BUT THERE IS POOR PENETRATION INTO THE CNS.|THE DRUG HAS A BIPHASIC PLASMA-DECAY CURVE WITH AN INITIAL HALF-LIFE OF 22 MIN (PROBABLY ELIMINATION) IN DOGS. HIGH TISSUE CONCNS HAVE BEEN FOUND IN KIDNEY, LIVER, OVARY, TESTIS, & UTERUS.|AFTER IV INJECTION OF ANIMALS WITH CISPLATIN, PLASMA LEVELS DECLINE BIPHASICALLY. 24 HR URINARY EXCRETION OF PLATINUM IS EXTENSIVE WITH A FINAL URINARY RECOVERY OF 70-90%. PLATINUM IS INITIALLY DISTRIBUTED IN NEARLY ALL OF THE TISSUES, WITH THE HIGHEST LEVELS IN KIDNEY, LIVER, OVARY, UTERUS, SKIN & BONE, BUT THERE IS NO PREFERENTIAL UPTAKE OF PLATINUM BY TUMORS.|AFTER IV ADMIN, MANY SPECIES (RAT, MOUSE, DOG) SHOW THE SAME GENERAL ORGAN DISTRIBUTION. ALL TISSUES TAKE UP PLATINUM, FOLLOWED WITHIN THE FIRST HR BY AN ACCUMULATION IN KIDNEY, LIVER, MUSCLE & SKIN. AFTER 24 HR, TISSUE:PLASMA DRUG RATIOS ARE GREATER THAN 1 IN OTHER TISSUES; THESE ARE MAINTAINED FOR AT LEAST A WK IN DOGS ... UP TO 4 WK AFTER A SINGLE DOSE, PLATINUM IS STILL DETECTABLE IN KIDNEY, LIVER, SKIN & LUNG. ... 18 HR AFTER IV INJECTION /OF RADIOACTIVE PLATINUM/ INTO RABBITS, KIDNEY & LIVER SHOWED THE HIGHEST LEVELS OF RADIOACTIVITY.|For more Absorption, Distribution and Excretion (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (14 total), please visit the HSDB record page.

Cisplatin can react in a nonenzymatic manner with water in vivo to form monoaquo & diaquo species following dissociation of the chloride groups. These metabolites extensively bind to protein (>90%) & thus have minimal cytotoxicites but the non-protein bound, ultrafilterable reactive species are cytotoxic.

AFTER RAPID IV ADMIN /TO HUMAN PATIENTS/ THE DRUG HAS AN INITIAL ELIMINATION HALF-LIFE IN PLASMA OF 25-50 MIN; CONCN DECLINE SUBSEQUENTLY WITH A HALF-LIFE OF 24 HR OR LONGER.|THE DRUG HAS A BIPHASIC PLASMA-DECAY CURVE WITH AN INITIAL HALF-LIFE OF 22 MINUTES (PROBABLY ELIMINATION) IN DOGS.

Cisplatin appears to enter cells by diffusion. The chloride atoms may be displaced directly by reaction with nucleophiles such as thiols; replacement of chloride by water yields a positively charged molecule & is probably responsible for formation of the activated species of the drug, which then reacts with nucleic acids & proteins. ... High concns of the anion stabilize the drug, explaining the effectiveness of chloride diuresis in preventing nephrotoxicity. ... The platinum complexes can react with DNA, forming both intrastrand & interstrand cross-links. The N(7) of guanine is very reactive, & platinum cross-links between adjacent guanines on the same DNA strand; guanine-adenine cross-links also readily form. The formation of interstrand crosslinks is a slower process & occurs to a lesser extent. DNA adducts formed by cisplatin inhibit DNA replication & transcription & lead to breaks & miscoding. The ability of patients to form & sustain DNA-platinum adducts in peripheral white blood cells has been correlated with response to treatment, indicating that pharmacogenetic factors or environmental exposures common to tumor & normal tissues may influence response. At present, there is no conclusive association between a single type of biochemical DNA adduct & cytotoxicity. The specificity of cisplatin with regard to phase of the cell cycle appears to differ among cell types, although the effects on cross-linking are most pronounced during the S phase.|A poorly differentiated squamous cell carcinoma of the head & neck heterotransplanted to nude mice was used for analyses of chemotherapeutically induced cell cycle perturbations. The tumor in its later passages in nude mice, was treated with cis-platin. There was an initial incr of the fraction of cells in the S phase, concomitant with a redn of the fraction of cells in G0 + G1 phase. When these perturbations were normalized a transient incr of the fraction of cells in G2 + M phase was observed. Cisplatin caused an initial transient depression of DNA synthesis.|The cytokinetic response of 3 murine (AC) and human (GB-1 and GB-2) glioma cell lines to cis-platin was investigated by flow cytometry. Using the 5-bromodeoxyuridine-Hoechst technique, percentages of cultured glioma cells in the various phases of the cell cycle, and relative phase duration were calculated. In the presence of cis-platin IC10 (a concentration in which 10% inhibition of cell growth is induced as compared to controls), perturbations of the cell cycle in murine and GB-1 cells included G2 delay or block, decr transit velocity from G1 to S phase, and prolongation of G1 phase. The mean cell cycle time incr 1.4 times in murine and 1.6 times in GB-1 as compared to controls. In cis-platin IC50-treated GB-2 cells, the mean cell cycle time was prolonged 3 times longer than control; however, duration of each phase could not be calculated because of significant perturbation of cell cycle.|Studies have been carried out of the inhibition of ribonucleotide reductase (EC 1.17.4.1) purified from Escherichia coli by cis-platin. Under anaerobic conditions, using the dithiol reduced form of the enzyme, it was found that ribonucleotide reductase is extremely sensitive to cis-platin; > 90% inhibition was achieved with 2 fold molar excess of platinum reagent even at 10-8 M enzyme. Inhibition was essentially instantaneous and irreversible to G-25 gel filtration. The site of inhibition was found to be the B1 subunit. Transplatin was much less effective. Inhibition of the enzyme by cis-platin (molar ratio cis-platin:B1 = 4.3) led to a decr in thiol titre corresponding to approx 1 thiol group per dimer of B1 subunits under conditions leading to 94% inactivation of the ribonucleotide reductase activity.|For more Mechanism of Action (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (10 total), please visit the HSDB record page.

No antidotes have been established for cisplatin overdosage. Hemodialysis is not useful in eliminating platinum from the body, but plasmapheresis lowers the plasma platinum concn. Management is based on supportive & symptomatic treatments.|Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

Sixty-nine gynecologic oncology patients received cis-platinum @ 4 wk intervals. Forty-one patients developed hypomagnesemia; 31 of these developed signs & symptoms of peripheral neuropathy. It was concluded that the symptoms were dependent on the total dose received by a patient.|An anaphylactic response to cisplatinum chemotherapy reported in a middle-aged man treated with intravesical cisplatinum for superficial transitional cell carcinoma of the bladder.|Patients treated /iv/ by isolated hyperthermic lower limb perfusion with cis-platinum showed peripheral nerve damage, particularly of the lower leg and foot. There was a close correlation between the severity of neurological deficit and the perfusion temperature.|In a study of 37 patients receiving /iv/ 50 mg/sq m of cis-platinum every 3 to 4 wk, 46% of the patients were noted to have ototoxicity. 14% showed a hearing loss in the speech frequency range.|For more Human Toxicity Excerpts (Complete) data for CIS-DIAMINEDICHLOROPLATINUM (20 total), please visit the HSDB record page.

CISPLATIN (PLATINOL) IS AVAILABLE AS A LYOPHILIZED POWDER AND IN SOLUTION (1 MG/ML) FOR INJECTION|(VET): LYOPHILIZED POWDER IN 10 MG VIALS. ONCE CONSTITUTED, THE SOLN SHOULD BE KEPT AT ROOM TEMP.|Vials for injection containing 10, 25 or 50 mg

Platinum, diamminedichloro-: INACTIVE|Cisplatin has been shown to have trypanocidal effects.

A reversed phase ion pair chromatographic method with on-line radioactivity detection for the simultaneous determination of (195m)Pt-labelled cis-platin and related platinum complexes was developed. The method was tested in animal and in vitro experiments. A good resolution of various radiolabelled platinum complexes was achieved. The detection limit of the radioactivity detector is 10 ng of cis-platin (specific activity of 15 MBq/mg cis-platin) per ml of urine or plasma ultrafiltrate. The detector response is independent of both the chemical structure of the platinum complexes and the matrix composition of the samples. This method may serve as a reference system for other high performance liquid chromatography systems with less specific and sensitive detectors.|A high performance liquid chromatographic (HPLC) method for the separation of cisplatin and its biotransformation products was evaluated using Sprague-Dawley-rats. Cisplatin eluted with a retention volume of 3.6 milliliters (ml) and its derivatives were eluted with retention volumes of 7.6 to 9.6 ml. Urine samples from eight rats treated with cisplatin showed a major peak corresponding to cisplatin, with similar elution profiles obtained from 3 minutes to 24 hours after injection.|A method was developed for detecting platinum complexes by liquid chromatography with quenched biacetyl phosphorescence detection. High performance liquid chromatography (HPLC) of cisplatin was based on a solvent generated anion exchange system with quenched phosphorescence detection. Analyses were performed on columns prepared by material coated with hexadecyltrimethylammonium/bromide. The quenched phosphorescence detection method was based on measuring room temperature phosphorescence of biacetyl present as a solute in the deoxygenated eluent. Analytes interacted with biacetyl to cause a decrease in phosphorescence signal intensity. Concentrations of cisplatin were varied from 2.5 to 7.5 umol/l. The developed method was applied to urine samples spiked with cisplatin. Peaks for cisplatin were clearly seen by the method with a retention time of 2.5 minutes. Detection limits were 0.3 umol/l for cisplatin.