Diammin[cyclobutan-1,1-dicarboxylato(2-)-O,O']platin

High-dose cisplatin regimens have been shown to be highly active in advanced melanoma patients but are associated with unacceptable side effects. In order to increase the platinum dose but avoid severe side effects, we treated 15 dacarbazine (DTIC)-resistant metastatic melanoma patients with a combination regimen of cisplatin (100 mg/sq m) and carboplatin (200 mg/sq m), two platinum analogues with a similar mode of action but a different toxicity pattern. After a mean follow-up period of 10.7 months (range 4-18 months), two patients (13.3%) achieved complete remission and two patients (13.3%) showed partial remission, giving an overall response rate of 26.4% (95% confidence interval [CI] 4.2-49%). Furthermore, three patients (20%; 95% CI 0-40.2%) experienced stable disease. The median duration of response was 7.1 months (95% CI 4.2-10.0 months), and the median overall survival was 12.5 months (95% CI 5.8-19.2 months), with eight patients still alive. The main side effects were haematological (leukopenia/thrombocytopenia World Health Organization [WHO] grade I-IV; anaemia WHO grade I-III), gastrointestinal (WHO grade I-III), neurological (WHO grade I-II) and renal (WHO grade I) toxicity. Nevertheless, except in one patient, side effects did not result in discontinuation of therapy. Despite the small number of patients treated in this preliminary study, we believe that combining cisplatin and carboplatin represents a novel, active and well-tolerated therapeutic option as second-line chemotherapy in DTIC-resistant advanced melanoma patients.

The nephrotoxic effects of different platinum compounds based combination chemotherapies were compared. Chemotherapy consisted of either cisplatin fractionated over 5 days (5 x 20 mg/sq m) or given as a single-day infusion (1 x 50 mg/sq m) plus ifosfamide (4 g/cu m) or high-dose chemotherapy was applied including carboplatin (3 x 500 mg/sq m) and ifosfamide (3 x 4 g/sq m) fractionated over three consecutive days. Conventional parameters such as serum creatinine and glomerular filtration rate (GFR), as well as urinary protein excretion of N-acetyl-beta-D-glucosaminidase (NAG)) and alpha 1-micro-globulin were assessed in 52 patients. Fractionation over 5 days without adding other nephrotoxic agents, ie ifosfamide, prevented decreases in glomerular filtration rate following cisplatin, whereas the combination of conventional dose cisplatin and ifosfamide, given as a single-day infusion, and high-dose carboplatin/ifosfamide yielded a pronounced fall of glomerular filtration rate. All groups showed increases in the urinary excretion levels of serum derived proteins and N-acetyl-beta-D-glucosaminidase, but with significant differences; about 2 to 3-fold for 5-days cisplatin, 3 to 5-fold for single-day cisplatin/ifosfamide, and 20 to 35-fold for high-dose chemotherapy. Thus, conventional approaches can reduce but not prevent the nephrotoxicity of cisplatin-based chemotherapy. In particular, high-dose chemotherapy regimens including carboplatin and ifosfamide are associated with comparable or even higher nephrotoxicity to single-day cisplatin/ifosfamide.

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is one of the tumor necrosis factor ligand families and it selectively induces apoptosis against cancer cells. Several cytotoxic anticancer drugs also mediate apoptosis and may share the common intracellular pathways leading to apoptosis. We reasoned that combination treatment of cancer cells with TRAIL and drugs may overcome this resistance. ... Treatment of T24 cells with a combination of TRAIL and cisplatin resulted in a synergistic cytotoxic effect. Synergy was also achieved in the cisplatin resistant T24 line (T24/CDDP), 2 other bladder cancer lines and 3 freshly derived bladder cancer cells. The combination of TRAIL and carboplatin resulted in a synergistic cytotoxic effect on T24 cells. However, the combination of TRAIL and trans-diamminedichloroplatinum (II) resulted in an antagonistic cytotoxic effect. The synergy achieved in cytotoxicity with TRAIL and cisplatin was also achieved in apoptosis. Treating T24 cells with cisplatin enhanced the expression of bax but not bcl-2. Incubation of T24 cells with TRAIL increased the intracellular accumulation of cisplatin. CONCLUSIONS: This study demonstrates that combination treatment of bladder cancer cells with TRAIL and cisplatin overcomes their resistance. The sensitization obtained with established cisplatin resistant and freshly isolated bladder cancer cells required low subtoxic concentrations of cisplatin, supporting the in vivo potential application of a combination of TRAIL and cisplatin for treating TRAIL resistant and cisplatin resistant bladder cancer.

Mild and transient elevations in serum aminotransferase levels are found in up to one-third of patients taking carboplatin. However, clinically apparent acute liver injury from carboplatin is extremely rare and the characteristics of such injury have not been well defined. In addition, carboplatin has been used in combination with other alkylating agents in high doses in conditioning regimens in preparation of hematopoietic cell transplantation which may be associated with instances of sinusoidal obstruction syndrome, which can be severe and lead to acute liver failure. Onset of sinusoidal obstruction syndrome is generally within 10 to 20 days of transplantation and presents with right upper quadrant pain, hepatic tenderness, weight gain, edema and ascites, followed by jaundice. The role of carboplatin in causing these cases of sinusoidal obstruction syndrome has not been well defined.

Acute toxicity: nausea & vomiting. Delayed toxicity: Bone marrow depression; peripheral neuropathy (uncommon); hearing loss; transient cortical blindness; hemolytic anemia. /From table/

... Carboplatin, cis-diammine(cyclobutane-1, 1-dicarboxylato)platinum(II) has been shown to be an active agent for acute myeloid leukemia. This second-generation platinum drug has less nephrotoxicity and ototoxicity but more myelotoxicity than does the first-generation platinum drug cisplatin. The study was designed to elucidate whether their myelosuppressive activities equal their antileukemic effects. ... Cisplatin and carboplatin were used to treat four leukemic cell lines (CEM, HL60, K562 and U937), blast cells from 10 leukemic patients and hematopoietic progenitors from five umbilical cord blood samples. ... The mean IC50 of leukemic cell lines was 0.4 and 6.2 ug/ml, the mean IC50 of patients' leukemic blasts was 2.0 and 22.4 ug/ml and the mean IC50 of hematopoietic progenitors (BFU-E, CFU-E and CFU-GM) was 1.8 and 1.7 ug/ml for cisplatin and carboplatin, respectively. ... Carboplatin required a 10 times higher drug concentration than cisplatin to induce a similar degree of growth inhibition on leukemic cells. However, the hematopoietic progenitors responded equally to cisplatin and carboplatin at the same drug concentration. The results suggest that the myelosuppressive activity of carboplatin is greater than its antileukemic effect.

Telomerase is a ribonucleoprotein enzyme which is involved in the maintenance of chromosome ends. Telomerase activity is frequently associated with malignant phenotypes, and it can be considered a ubiquitous tumor marker. In this study we describe an approach for developing in vitro chemosensitivity assays based on the assessment of telomerase activity in squamous cell carcinoma to treatment with anticancer drugs. ... A431/CDDP1 and A431/CDDP2, two previously established cisplatin (CDDP)-resistant A431 sublines /were used/. These cell lines were not multidrug resistant but specifically resistant to the CDDP drug family. The telomeric repeat amplification protocol (TRAP assay) was used to measure telomerase activity in CDDP-resistant cell lines and to examine the effect of CDDP and other anticancer drugs on enzyme levels. We next analyzed the relations between telomerase activity and cytotoxic effects of CDDP in human squamous cell carcinoma (HSC2, HSC3, HSC4 and KB cell lines). RESULTS: The telomerase activity of A431/CDDP1 and A431/CDDP2 was significantly higher than that of the parent A431 cell (A431/P) treated with CDDP and carboplatin at IC(50). On the other hand, telomerase activity in these cell lines was not influenced by treatment with 5-fluorouracil, bleomycin, Adriamycin or taxol. The regression line derived from the quantitative analysis of the telomeric ladder versus IC(50) of CDDP concentrations was analyzed. Telomerase activity was found to be positively correlated with the IC(50) values for CDDP. ... The results of the present studies on in vitro squamous cell carcinoma cell lines indicate that telomerase activity inhibition can be used as a marker of tumor cell killing by CDDP. Therefore, the present investigation provides a rational basis for an in vitro chemosensitivity assay based on telomerase activity evaluation.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Carboplatin

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

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/

Rat(iv): LD50: 61 mg/kg

Mouse(ip): LD L0: 150 mg/kg

Mouse(iv): LD50: 143 mg/kg

LD50 Rat oral 343 mg/kg

LD50 Rat sc 72 mg/kg

LD50 Rat iv 61 mg/kg

LD50 Mouse ip 118 mg/kg

LD50 Mouse iv 89,360 ug/kg