Iproplatin

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropvlamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25]. 

The diisopropylamine complex (a) has undergone clinical trials as the drug iproplatin (CHIP) the simple ammonia analogue (b) oxoplatin has shown promising anti-tumour activity (see also section 3.10). 

Figure 3.116 Platinum compounds studied for possible anti-tumour activity. I, ris-Dichlorodi-ammineplatinum(II) cisplatin, platinol NSC 119875 neoplatin platinex. II, a.s-Diammine(l,l-cyclobutanedicarboxylato)platinum(II) JM-8 paraplatin NSC 241240. Ill, Oxiplatin. IV, Tetraplatin. V, Amminediacetatodichloro(cyclohexylamine)platinum(IV). VI, cis-Dich oro-trans-dihydroxy-cis-bis(isopropylamine)platinum(IV) iproplatin JM-19 CHIP NSC 256927.

Platinum is used therapeutically as ds-platin, carboplatin and iproplatin against tumors (Konig and Schuster 1994). Determination of Pt in serum must be carried out after enrichment procedures followed by GF-AAS. 

Figure 7.9 Other platinum-containing anticancer agents evaluated in clinical trials. (A) Oxaliplatin, Pt(II) (B) ZD0473, Pt(II) (C) iproplatin, Pt(IV) (D) ormaplatin, Pt(IV).

Platinum (IV) Structures. The oxidation state of the platinum atom in platinum coordination compounds determines the steric configuration of the molecule platinum(II) structures are planar molecules, while platinum(IV) derivatives assume an octahedral shape. Though it was hoped that these differences could be used to circumvent platinum resistance, the two compounds developed in the clinic, iproplatin and ormaplatin, have not proven useful. In the case of the former, testing in Phase-II trials failed to reveal activity. In the case of ormaplatin, the platinum(IV) configuration is not maintained under biological conditions conversion to a platinum(II) metabolite occurs within minutes [14], A series of novel platinum(IV) and mixed ammine/amine derivatives being developed at the Institute for Cancer Research are described in this volume by Kelland. 

Cervical and Endometrial Cancer. Cisplatin is one of the most active agents available for the treatment of squamous-cell cancers of the cervix. Single-agent trials have indicated response rates of up to 31% in patients with advanced disease, with nearly one-third being complete responses [186], The GOG reported the results of a large (394 patients) randomized trial in 1989 comparing carboplatin and iproplatin monotherapy and noted a 15% response rate with carboplatin, suggesting that its activity may not be comparable to cisplatin in cervical cancer [187]. 

Figure 7 Pt(IV) complexes satraplatin (8), iproplatin (9), and ormaplatin (10) and the sterically hindered Pt(II) complex ZD0473 (11)...

Cheung Y, Cradock JC, Vishuvajjala BR, Flora KP. Stability of cisplatin, iproplatin, carboplatin and tetraplatin in commonly used intravenous solutions. Am J Hosp Pharm 1987 44 124 130. 

Lind MJ, McGregor J, Timms MS, Brown D, Palmer P. Comparative toxicity of cisplatin, carboplatin (CBDCA) and iproplatin (CHIP) in combination with cyclophosphamide in patients with advanced epithelial ovarian cancer. Eur J Cancer Clin Oncol 1988 24(9) 1471-9. 

CHIP iproplatin. chitan poliglusam. chitin poliglusam. 

C/S-DlCHLORO-77t4JVS-DIHYDROXOBIS(ISOPROPYLAMINE)PLATINUM(lV) (IPROPLATIN) 146... 

C/S-DICHLORO-77L4AS-DIHYDROXOBIS(ISOPROPYLAMINE)-PLATINUM(IV) (IPROPLATIN), (17)... 

A clue to the nature of the mechanism by which Pt(IV) compounds exert their antitumour effects was uncovered in clinical trials involving iproplatin [122]. 

Potency. Nearly all of the platinum(IV) complexes tested are less potent than cisplatin, with the single exception of (25) [74]. Iproplatin is 4-16-times less potent, with multidose schedules tending toward the higher number whether measured by antitumour O.D. or LDS0 determinations. Oxoplatin, (23), is likewise about 10-times less potent than cisplatin. 

Toxicity. Iproplatin has less renal toxicity than cisplatin in rats at levels eliciting comparable gastrointestinal and bone marrow toxicity [139]. Similar results were seen in mice, where (17) caused severe leukopoenia but no azotaemia at high doses [97]. Studies in dogs indicated that iproplatin caused vomiting to about the same extent as cisplatin [48]. 

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