Comparative assessment of clinical trials, indications, pharmacokinetic parameters and side effects of approved platinum drugs

Platinum complexes are among the most commonly applied anticancer agents. The aim of current work is collection, analysing and comparative estimation of clinical trials and pharmacological indications of currently approved for application platinum detivatives: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin (Japan), Lobaplatin (China), Heptaplatin (North Korea), and Satraplatin. The other aim of the study includes the summarizing of the hystoric data for the stages of the developlement of these drugs, and the comparison of pharmacokimetic parameters, side effecs and the dose-liniting factors of the drugs. The observational study on pharmacokinetic parameters shows that protein binding decreases in order: 95% (Cisplatn); 90% (Oxaliplatin); 50% (Nedaplatin); low (Carboplatin). For every of Cisplatin, Carboplatin, Oxaliplatin have been reported more than 1000 clinical trials; for Lobaplatin, Nedaplatin, Satraplatin about 10 trials. The differenses in dose-limiting effects are: neuro-, nephro-, ototoxicity (Cisplatin); neurotoxicity (Oxaliplatin); nephrotoxicity (Heptaplatin); myelosuppression: thrombocytopenia, neutropenia, leukopenia (Carboplatin, Nedaplatin, Satraplatin).


Introduction
Malignant tumors are the leading cause of lethality worldwide, and are a group of more than 100 different types of diseases, that are characterized by uncontrolled cell growth, local tissue invasion and distant metastases. The incidence of malignant tumors is enlarging, with the fastest increasing of lung, prostate, and colon cancers in men and breast carcinomas in women. Malignant tumors originate from different types of tissues: connective, epithelial, hematopoietic, lymphoid, nervous. Tumor cells are characterized by high mitotic and proliferative activity, have a shorter cell cycle duration, and a lower rate of cell death. The main difference between a normal and a tumor cell is the continuous tumor growth. Highly differentiated tumors have slower growth, metastasize relatively less frequently and later, and are less sensitive to cytostatics. Poorly differentiated cells proliferate rapidly, metastasize to distant organs, and are sensitive to cytostatics.
In carcinogenesis (oncogenesis, tumorigenesis) normal cells are transformed into cancer cells. This multistage process involves changes at the cellular and genetic levels, and involves initiation, promotion, malignant formation, progression, local tissue invasion and metastases. Initiation is characterized with the alteration, change, or mutation of genes. Genetic alterations are result from dysregulation of biochemical signaling pathways, associated with cellular proliferation, survival, and differentiation. The actively proliferating preneoplastic cells accumulate in the promotion stage. Progression is the final stage of neoplastic transformation, and is the phase between a premalignant lesion and the development of invasive cancer. Fast increase in the tumor size, genetic and phenotypic changes, and cell proliferation occur in progression phase. Metastasis is the spread of cancer cells through the bloodstream or the lymph system, from the primary site to other parts of the body (Siddiqui et al. 2015).
The most significant risk factor for the development of cancer are genetic and environmental factors (Saeki and SugiIchi 2001) and old age (Anisimov et al. 2009). DNA damage is considered to be the primary cause of cancer. At the molecular level, tumors are considered a mutation in somatic cell DNA, caused by various carcinogenic factors. In this process, various genetic and epigenetic tumor-specific mutations occur, which define the biological features of tumor growth: uncontrolled cell proliferation, invasion of neighboring tissues and metastasis of cells to distant tissues. The main reasons for the transformation of a normal cell into a malignant one are: conversion of proto-oncogenes into oncogenes, inactivation of tumor suppressor genes (p53, RAS), and dysregulation of positive and negative signals for proliferation. Genetic abnormalities include the following genes (Saeki and SugiIchi 2001): I. cell cycle genes: p53 (brain and breast cancer); p16 (melanoma); Rb1 (retinoblastoma); VHL (renal cancer); WT1 (Wilms cancer) II. DNA repair genes: BRCA1, BRCA2 (breast cancer); MLH1, MSH2, MSH6, PMS1, PMS2 (colon cancer); XPA, XPB, XPC, XPD, XPF, XPG (skin cancer) III. signal transduction genes: MET (papillary renal cell carcinoma); NF1 (neurofibroma); RET (adrenal pheochromocytoma) IV. genes responsible for tissue organization: APC (colon cancer); E-cadherin (gastric cancer); NF2 (neurinoma).
DNA damage can also be caused by substances, produced in the body. Macrophages and neutrophils in an inflamed colonic epithelium initiate colonic tumorigenesis (Anisimov VN et al. 2009), due to the DNA damage by reactive oxygen species. In high-fat diet, high levels of bile acids cause DNA damage, and contribute to colon cancer (Bernstein et al. 2011).
DNA damage can arise too from exposure to exogenous environmental carcinogenic agents: I. Physical factors 1 ionized radiation: gene mutation or chromosome aberration in lung and thyroid cancer 2 UV-light from solar radiation: DNA damage in melanoma (Kanavy and Gerstenblith 2011) II. Chemical factors 1 benzo-pyrene: from tobacco smoke (Kuper et al. 2002): lung cancer, due to mutation in the p53 gene, a tumor suppressor gene, which is considered to be one of the mechanisms of carcinogenesis (Saeki et al. 2000) 2 ethyl alcohol: esophageal cancer, due to p53 gene abnormalities (Saeki et al. 2000) 3 cadmium: prostate cancer. (Irigaray et al. 2007) 4 Aspergillus flavus metabolite aflatoxin: liver cancer (Smela et al. 2002) (Samaras et al. 2010).
Cytotoxic chemotherapy has proven useful in a number of different cancer types including: lung, pancreatic and colorectal ca Concer (Corrie 2008). One of the most commonly used cytostatics are platinum complexes (Wheate et al. 2010).
In the following tables are summarized produsers (Table 1.) and names (Table 2.) of approved platinum drugs.
The development of the therapy is presented in Table  3. (Cisplatin and Carboplatin) and in Table 4. (other approved Cisplatin derivatives).  Cisplatin as Peyrone's chloride has been prepated by the Italian chemist Michele Peyrone For the generic Cisplatin Hospira, the approved indication spectrum is wider than that authorised by FDA (advanced or metastatic testicular, ovarian and bladder cancer), and includes: non-small and small cell lung carcinoma, squamous cell carcinoma of the head and neck, and cervical carcinoma, when combined with chemo-or radiotherapy. In Germany Platinex has been approved on for treatment of testicular, ovarian, and bladder cancer. The indication spectrum for Carboplat is for epithelial ovarian cancer, small cell lung carcinoma, squamous carcinoma of the head and neck, and metastatic cervical and ovarian cancer. In Austria Carboplatin indications includes: bladder cancer, squamous carcinoma of the head and neck, non-small cell lung cancer, and cervical carcinoma (Kalayda 2020).
The chemical structures of approved platinum drugs are illustrated on Table 5., and in Table 6. are summarized the most important pharmacokinetic parameters.
Cisplatin is binding to plasma proteins: gammaglobulin, albumin, transferrin, and 90% of the plasma platinum is protein-bound 2 h after 3 h infusion. Cisplatin concentrations are highest in liver, kidney, prostate; lower in muscle, pancreas, spleen, bladder, and lowest in cerebrum, cerebellum, lung, heart, adrenal. In tissues platinum is present 6 months after the last administration. The complexes between albumin and Cisplatin do not dissociate to a significant extent, and are eliminated slowly with a minimum half-life of 5 days or more.
The distribution half-life of Carboplatin is 1.1-2 h. Predominantly the drug is elimi-nated in the urine as the unchanged parent compound: 65% within 12 h, 71% within 24 h; 5% from 24 h to 96 h, withouth biliary elimination. The total body clearance after a 30 min. intravenous infusion of 500 mg/m 2 is 4.4 l/h (Reece et al.1987). Oxaliplatin plasma protein binding is primarily to albumin and gammaglobulins. The drug also irreversibly binds to erythrocytes. At the end of a 2 h infusion of Oxaliplatin, 15% of the administered platinum is present in the systemic circulation, and 85% is rapidly distributed into tissues or eliminated triphasic in the urined -t ½ α = 0.43 h, t ½ = 16.8 h, t ½ γ = 391 h (Levi et al. 2000). The excretion of Nedaplatin is renal (59.6%) (Sasaki et al. 1989;Ishibashi et al. 2003).
The indications for the approved platinum drugs are presented in Table 7. Confirmation of cis-geometry of Cisplatin by an X-ray method.

1968
The earliest pvoved activity of Cisplatin against model mice timors.

1970
Cisplatin enters clinical trial in non-small cell lung cancer.

1971
The earliest application of Cisplatin in patients.

1975
The beginning of Phase II clinical trials for Cisplatin.

1978
The approval of Cisplatin by the Food and Drug Administration.

1978
The authorisation of Platinol.

1979
The intraduction for Cisplatin in the United Kingdom.

1979
The approval for Platinex in Germany.

1985
Description of various cisplatin-induced adducts formed on DNA.

1987
The authorisation for Cisplatin in Austria.

1991
Role of elevated glutathione in inducing tumor resistance to Cisplatin.

1996
The generic Cisplatin Hospira receives marketing authorisation.

1998
The intraduction for Cisplatin as generic product of Teva Sante in France.
1999 Identification of the molecular defect that causes hypersensitivity of some testicular cancers to Cisplatin.

2002
Identification of the role of the CTR1 in transporting Cisplatin into cells.

1982
The earliest application of Carboplatin in patients.

1988
The approval of Carboplat in Germany.

1989
The authorisation of Carboplatin by FDA (ovarian cancer).

1989
The introduction from FDA of Paraplatin (Bristol-Myers Squibb) 1990 The approval of Carboplatin in the United Kingdom for ovarian carcinoma.

1992
The authorisation in France of Carboplatin, developed by Pfizer.

1995
The introduction of Carboplatin in Austria.

2006
FDA regulatory approval of Bevacizumab for the treatment of non-small cell lung cancer in combination with Carboplatin and Paclitaxel.  (Totani et al. 1986) 1998 The approval of Nedaplatin for clinical application in Japan.

Picoplatin (Kalayda 2020)
1997 The earliest Picoplatin administration in patients with small cell lung cancer.

Satraplatin (Kalayda 2020) 1993
Oral administration for the first time of Satraplatin to patients.

2007
Satraplatin FDA regulatory approval for the treatment of prostate cancer. The data for the clinical trials are shown on Table 8. (Cisplatin, Carboplatin, Lobaplatin) and on Table 9. (Oxaliplatin, Nedaplatin, Satraplatin).
Neurotoxicity is the most important adverse effect of Cisplatin chemotherapy in 47% of patients Symptoms include numbness, tingling, paraesthesia in the limbs, difficulty walking, decreased sensation of tendon reflexes Neuropathy is long-term with significant worsening of symptoms during the first 4 months, which may continue 52 months after stopping treatment. Higher concentrations in peripheral nervous system tissues (peripheral nerves and dorsal root ganglia), compared to central nervous system tissues (brain, spinal cord) correlate with clinical symptoms of peripheral neuropathy.
Toxicity of platinum compounds is presented on Table 10 (Hartmann and Lipp 2003).