DNA Alkylator/Crosslinker

Cisplatin has proven to be effective in slowing down the growth of tumors in a range of animal tumor models, such as xenografts of head and neck cancer, testicular carcinoma, ovarian cancer, breast cancer, colonic carcinoma, heterotransplanted hepatoblastoma, and so forth. Tumor growth inhibition (GI) is induced in 77.5% and 85.1% of the serous xenografts Ov.Ri(C) and OVCAR-3, respectively, by weekly intravenous treatment with cisplatin (5 mg/kg).[6]

L1210/0 cells are kept in an exponential suspension culture in McCoy's medium 5a (modified), supplemented with 15% calfserum and Fungizone, at 37 °C in a humidified atmosphere of 5% CO₂. For two hours at 37°C, L1210/0 cells are incubated in 7 μg/mL of cisplatin. The cells are centrifuged, once again cleaned, resuspended in fresh medium at 30 × 10³ to 50 × 10³ cells/mL, and incubated for three days in order to measure growth inhibition. A Coulter Counter is used to calculate cell numbers. Trypan blue (0.4% volume) is added to an aliquot of cells to dilute it. The percentage of cells that have not included trypan blue is used to determine viability. Colonies are counted after two weeks of growth for cells cultured with Cisplatin as previously described, after which they are diluted into 0.1% agar.

Mice: There are twenty mice per group, which are randomly assigned to three groups: Control, Cisplatin, and Cisplatin+HemoHIM. A subcutaneous femoral left region in mice is injected with B16F0 melanoma (5×10⁵ cells/mouse) three days prior to the first Cisplatin injection. Three injections of 4 mg/kg body weight (B.W.) of cisplatin are administered intraperitoneally on days 0 through 14. Day 0 to Day 16 see daily intubations of the experimental group with HemoHIM at a final concentration of 100 mg/kgB.W., while the control group was given only water. Each group's mice undergo experiments on day 17 following their first Cisplatin injection in order to assess the tumors' size or weight. The tumor size is calculated as follows: tumor size=ab²/2, where a and b are the larger and smaller diameters, respectively.
Rats: Four groups of four or five male Sprague-Dawley rats, weighing 200 to 250 g apiece, are randomly assigned. First, a vehicle containing 5% carboxymethyl cellulose sodium solution (CMC-Na), 5 mL/kg body weight, p.o., was administered to the control group (Cap). The third group was injected with 5% CMC-Na for six consecutive days along with 5 mg/kg of Cisplatin in physiological saline solution intraperitoneally (i.p.). The second group received Cap (10 mg/kg/d, p.o.) in 5% CMC-Na (5 mL/kg). Six days straight after receiving an injection of 5 mg/kg of Cisplatin intraperitoneally (i.p.), the fourth group was given Cap (10 mg/kg/d, p.o.) in 5% CMC-Na. Every group receives a cap or vehicle twice a day. Data from our preliminary experiments are used to determine the chosen Cap concentration and the dose administration schedule without causing any intestinal damage in rats.

Absorption, Distribution and Excretion
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.

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Metabolism / Metabolites
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.

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Biological Half-Life
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.

Toxicity Summary
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.

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Interactions
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.

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Non-Human Toxicity Values
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.

[1]. Oncogene . 2003 Oct 20;22(47):7265-79.

[2]. Biol Chem . 2000 Dec 15;275(50):39435-43.

[3]. Cancer Res . 1988 Aug 15;48(16):4484-8.

[4]. J Pharmacol Exp Ther . 2002 Jul;302(1):8-17.

[5]. Am J Physiol . 1996 Apr;270(4 Pt 2):F700-8.

[6]. Int J Cancer . 1992 Apr 22;51(1):108-15

[7]. Cancer Res . 2014 Jul 15;74(14):3913-22.

See also: Cisplatin (annotation moved to).

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Mechanism of Action
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.

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Therapeutic Uses
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.

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Drug Warnings
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.

CL2H6N2PT

300.05

296.939

Cl, 23.63; H, 2.02; N, 9.34; Pt, 65.02

15663-27-1

2767

Yellow solid powder

3.7

270ºC

1.595

2

2

0

5

7.6

0

[Cl-][Pt]([NH3+])([NH3+])[Cl-]

LXZZYRPGZAFOLE-UHFFFAOYSA-L

InChI=1S/2ClH.2H3N.Pt/h2*1H;2*1H3;/q;;;;+2/p-2

(SP-4-2)-diamminedichloroplatinum; platinum, diaminedichloro-, cis-

Cismaplat; Cisplatina; cisplatinous diamine dichloride; cisplatinum; cisplatinum II; cisplatinum II diamine dichloride; CDDP; DDP; cisDDP; cisdiamminedichloro platinum (II); cisdiamminedichloroplatinum; Cisdichloroammine Platinum (II); CPDD; Cysplatyna; DDP; PDD; Peyrones Chloride; Peyrones Salt; CACP; Platinoxan; platinum diamminodichloride. Trade names (US): Platinol; PlatinolAQ. Trade names (other countries): Abiplatin; Blastolem; Briplatin; Cisplatyl; Citoplatino; Citosin; Lederplatin; Metaplatin; Neoplatin; Placis; Platamine; Platiblastin; PlatiblastinS; Platinex; Platinol AQ; PlatinolAQ VHA Plus; Platiran; Platistin; Platosin.

2843.90.0000

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 10 mg/mL (33.33 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 20 mg/mL (66.66 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: Saline: 3 mg/mL

 (Please use freshly prepared in vivo formulations for optimal results.)