The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclea...

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Free radical formation by antitumor quinones

Cisplatin was discovered to have cytotoxic properties in the 1960s, and by the end of the 1970s it had earned a place as the key ingredient in the systemic treatment of germ cell cancers. Since the early seminal work in the preclinical and clinical development of this drug, several thousand analogues have been synthesised and tested for properties that would enhance the therapeutic index of cisplatin. About 13 of these analogues have been evaluated in clinical trials, but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. However, carboplatin has afforded benefit only in reducing some cisplatin toxicities; it has not enlarged the spectrum of platinum-sensitive cancers, nor has it proved active in cisplatin-resistant cancers. The major obstacle to the efficacy of cisplatin or carboplatin is platinum resistance, either innate or acquired. The mechanisms of this resistance have been under intense study, and many of the cisplatin analogues synthesised in the past decade have been designed specifically with the hope of overcoming platinum resistance. The mechanism of the cytotoxic activity of platinum complexes has also been studied intensely. Recently synthesised analogues have been designed to interact with DNA in a manner different from cisplatin and carboplatin, with the desire of finding new structures with a superior or wider spectrum of antitumor efficacy. Most recently, water soluble platinum complexes that retain antitumour activity, but that can be effectively absorbed after oral administration, have been synthesised with the goal of improving patient quality of life. Nine platinum analogues are currently in clinical trials around the world (ormaplatin [tetraplatin], oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 [NK-121], 254-S, JM-216 and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) [LNDDP]). Some of these analogues only represent attempts to reduce cisplatin toxicity and/or allow administration without forced hydration and diuresis, which carboplatin already does. Others are 'third generation' complexes shown to have limited or no cross-resistance with cisplatin in preclinical studies. They are being tested clinically with particular attention to this highly desirable property.(ABSTRACT TRUNCATED AT 400 WORDS)

New cisplatin analogues in development. A review.

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to...

The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity

https://www.ajkd.org/article/S0272-6386(86)80112-3/pdf

Nephrotoxicity Induced by Cancer Chemotherapy With Special Emphasis on Cisplatin Toxicity

Antitumor activity and toxicity of cisplatin analogs.

A series of 30 different N7-phenyl-substituted mitomycin C analogues, including 25 new compounds, was prepared from mitomycin A. Seven of these compounds were clearly superior to mitomycin C in activity against P-388 murine leukemia. The para- and the meta-substituted derivatives were subjected to Hansch analysis, which revealed that the lipid-water distribution coefficient pi was the only significant factor in determining antitumor potency (MED). The substituent electronegativity factor sigma was statistically insignificant in determining potency, despite the good correlation of sigma p with the polarographic quinone-reduction potential. These results suggest that diffusion into the tumor cell or access to the receptor is more important than bioreductive activation in determining antitumor potency for this particular group of mitosanes . Fifteen new mitomycin C analogues with heterocycles on the 7-amino group also were prepared. Two of them, containing pyrazolyl and aminopyridyl substituents, were more active than mitomycin C against P-388 murine leukemia. No broad correlations could be made among the antitumor potencies and physicochemical properties for this type of analogue.

Mitomycin C analogues with aryl substituents on the 7-amino group.

A series of 7-(2-substituted-ethyl)amino analogues of mitomycin C and porfiromycin was prepared and screened in standard antitumor systems. Certain of these analogues showed better activity than mitomycin C against P-388 leukemia, L-1210 leukemia, and/or B-16 melanocarcinoma in mice. Compounds also tested for their leukopenic effects in mice, the limiting toxicity of mitomycin C. Some of them were less leukopenic and some were more leukopenic than this clinical agent. No statistically significant correlations could be made between physicochemical properties and antitumor activities of the analogues.

Mitomycin C and porfiromycin analogues with substituted ethylamines at position 7.

Toxicology screening in small animals

A series of mitomycin C analogues with secondary amines at position 7 was prepared from mitomycin A. Eleven of the 20 new compounds in this series were more active than mitomycin C against P-388 murine leukemia, and 2 of these 11 were significantly less leukopenic. The two substituents conferring these superior properties were 4-formylpiperazine and 2-cyanoaziridine. No quantitative correlations could be made among antitumor activities and physicochemical properties of the analogues, although the relative ease of quinone reduction might be related to the good potencies (minimum effective doses) of many of them.

Mitomycin C analogues with secondary amines at position 7.

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