Analogues

The design and developement of these cisplatin analogues have revealed common requirements that are necessary for its use as an anticancer drug. These common factors are:

• Electroneutrality, to allow for it to pass through non-polar substances such as cell membranes;
• Presence of at least two good leaving groups, preferentially cis to one another. This allows for DNA and/or protein binding.
• Presence of "inert" carrier ligands, usually non-tertiary amine groups which increase adduct stabilisation through hydrogen bonding with nearby bases. (Dr. S. James, 1998) ^‡

If these criteria are satisfied or present in a platinum complex, it is most likely going to be active. With such relatively broad requirements, new platinum based anticancer drugs can therefore, have totally different structures to cisplatin. This fact has not gone un-noticed. There have been developements of octahedral platinum(IV) complexes, one of which is in clinical use (iproplatin), trans-platinum complexes, and even talk of bis-platinum complexes! ^‡ The theory behind the later type being the ability to bind through two metal atoms instead of one. Such compounds should therefore, be more potent, and active over a larger spectrum of cancers, including cisplatin resistant types. A study of the complex [cis-PtCl₂(NH₃)]₂H₂N(CH₂)₄NH₂ showed it to be active against some cancer cells by forming covalent bonds with DNA and DNA repair proteins, thus separating the two and preventing repair.

A confusing report claimed that trans complexes are cytotoxic and maybe more so than cisplatin. ^¤ It mentioned anticancer activity of some trans complexes and possible modes of action, most of which, quite frankly, did not really suggest anything at all. Proposed mechanisms were frequently mentioned with uncertainty and little confidence, due to insufficent evidence and other weak reasons. For some strange reason, it was concluded that trans-platinum complexes were more active than cisplatin when most of the explanations were more to do with the mechanisms of cisplatin itself. One proposal that was suggested and is most likely to be accurate (an independent source confirms it), is that of the induction of protein-associated DNA strand breaks. This would cause eventual cell death via a mechanism similar to etoposide action. (See the indirect fourth mechanism).

The search for a less toxic agent was pursued at the Institute for Cancer Research in the United Kingdom and led to the development of carboplatin. Carboplatin (JM-8, paraplatin), or more accurately diammine(1,1-cyclobutane-dicarboxylato)platinum(II) (CBDCA for short), entered clinical trials on 1981 and showed a very similar activity profile to that of cisplatin, with good response in ovarian, small cell lung, head and neck, and testicular cancers.(Page et al 1992) It is now currently the second most widely used platinum anticancer drug in the world. ^{¤ , ‡ , ‡}

Carboplatin is supplied in 50mg/150mg/450mg vials and is reconstituted with sterile water, saline and 5% dextrose solution at room temperature, to a typical concentration of 10mg/ml. The standard dose is about 300mg/m², which is administered intravenously. Like cisplatin, carboplatin must not be administered with aluminium hubbed needles.

It is commonly referred to as the organic version of cisplatin, but with reduced toxicity and potency. Unlike its parent compound, carboplatin has myelosuppression as its dose-limiting factor. The drug is most toxic to the platelet precursors, where neutropenia and anaemia are frequently observed. The other toxicities of carboplatin are generally milder and better tolerated than those of cisplatin. Nausea and vomiting though frequent, is less severe, shorter in duration, and more easily controlled with standard antiemetics (for example, Compazine, dexamethasone, lorazepam) than that with cisplatin. At effective doses, carboplatin produced substantially reduced nephrotoxicity, otoxicity, neurotoxicity, and alopecia. ^‡ The reduced nephrotoxicity is believed to be due to the "inert" dicarboxylate ligands which allow for excretion as their unreacted forms. The lack of nephrotoxicity at standard doses means that extensive hydration is not required and in fact the drug may be administered in an outpatient setting.(Page et al 1993) The advantage in using carboplatin instead of the parent complex is therefore, clearly in its reduced toxic side effects.

The mechanism of action of carboplatin is very similar to that of cisplatin, forming preferrential cross-links with guanine in DNA thus eventually causing cell death. It may also interact with nuclear proteins, and is phase-nonspecific. Unfortunately, this explains why it is cross-resistant with the parent drug, and shows similar survival durations. ^{‡ , ‡} Tumours resistant to carboplatin are becoming more common, and like that of cisplatin, the cause of drug resistance is unclear. Preliminary results from a research group ^‡, suggest a mechanism where P53 is inactive due to genetic mutations.

Like the majority of second generation platinum-based drugs, carboplatin has a lower activity to that of cisplatin (see table below). A study has shown that with equimolar doses of carboplatin and cisplatin, the former was less effective than the latter with respect to ovarian cancer. ^‡ Comparative studies have also shown that carboplatin takes longer to bind to the nucleophilic sites of DNA than cisplatin. Work done at Ohio State University using Raman spectroscopy ^‡ showed that it would take three weeks for carboplatin to reach the same level of reaction that cisplatin reached in five days. This difference in rate indicates that for carboplatin to have the same efficacy as cisplatin, a larger dose must be given for a longer period of time. A study revealed that a doubling of the carboplatin dose would not show any significant improvement of pathologic remission or survival. ^‡ Myelotoxicity and neurotoxicity increased with higher doses, which was only feasible with growth-factor or stem-cell support. However, the actual recommended doses of carboplatin may be anywhere from four to ten times higher than for cisplatin, therefore, it is usually incorporated into high-dose intensity chemotherapy regimens.

Carboplatin is nevertheless, still used as an effective anticancer drug, because of its reduced toxicity and greater ease of administration. It is slowly replacing the use of cisplatin for certain cancers and situations where toxicity is a crucial factor.

The third most widely available drug related to cisplatin, is oxaliplatin. This compound is supplied in 50- and 100-mg glass vials, and is reconstituted with sterile water to yield a 2 mg/mL solution for intravenous administration. The dose-limiting factor is sensory neuropathy, which is again different to cisplatin, and is minimised by a split-dose schedule. Carboplatin is generally less toxic, with reduced myelosupprssion, nephrotoxicity and ototoxicity, however, nausea and vomiting remain acute, but respond well to antiemetics (5 HT3 antagonists).

The activity of oxaliplatin has been shown to have a more powerful pharmacological effect than cisplatin, ^‡ which is due to its different mechanism of action. ^† Studies indicate it attaches onto proteins which are vital for DNA transcription, thus preventing cell division and causing eventual cell death.

Other analogues in current clinical use include:

• Iproplatin (CHIP) or more formally (cis-dichloro-trans-dihydroxy-cis-bis(isopropylamine)platinum(IV)), ^¤ is also less toxic than cisplatin with respect to alopecia, the degree and duration of nausea and vomiting, renal toxicity, neurotoxicity and anaemia. ^‡ However, it caused the same cumulative toxicity on haemoglobin, leukocyte count and platelet count, and more thrombocytopenia, diarrhoea and leukopenia. Iproplatin has similar response rates, duration of response and survival to that of cisplatin.
• Tetraplatin (ormaplatin). Forms intrastrand cross-links but is less cytotoxic than cisplatin.
• JM118 (cis-amminedichloro(cyclohexylamine)platinum(II)). This has been shown to form intrastrand cross-links and have a greater cytotoxicity than cisplatin with respect to human ovarian carcinoma cells.
• JM149 (cis-amminedichloro(cyclohexylamine)-trans-dihydroxoplatinum(IV)). Forms intrastrand cross-links but is less cytotoxic than cisplatin.
• JM216 (bis-acetato-cis-amminedichloro(cyclohexylamine)platinum(IV)). Forms intrastrand cross-links but is less cytotoxic than cisplatin.
• JM335 (trans-amminedichloro(cyclohexylamine)dihydroxoplatinum(IV)). This has been shown to have comparable cytotoxicity to cisplatin, because not only is it able to form some intrastrand cross-links, it is also has the unique ability to form single strand breaks. ^‡
• Transplatin. This complex is very much lower in cytotoxicity than its cis counterpart, however, it has been shown to be more kinetically reactive. ^¤ The low cytotoxicity was proposed to be due to fast repairing of its interstrand cross-links, because the adducts do not resemble HMG-box binding sites.

• cis, trans, cis-Pt(NH₃)(C₆H₁₁NH₂)(OOCC₃H₇)₂Cl₂. This platinum complex has been designed specifically for oral administration. It is water-soluble, lipophilic and robust enough to survive the gastric environment. However, as it is a platinum(IV) complex, it will undergo relatively slow ligand substitution reactions compared with their platinum(II) analogues, therefore, they may have to be reduced to the kinetically more labile and reactive Pt(II) derivatives in vivo. Many studies have shown this to be possible, where platinum(IV) metal centers are readily reduced by cellular components such as glutathione and ascorbic acid to form the platinum(II) analogues that bind more rapidly to DNA.
• Nedaplatin (254S). This cytotoxic drug from Japan has been shown to be active in several solid tumors without renal toxicity. ^‡ The reported dose limiting toxicity is myelosuppression, especially thrombocytopenia.
• Malanato-1,2-diaminocyclohexaneplatinum(II).
• 5-Sulfosalicylato-trans-(1,2 diaminocyclohexane)Platinum(II) (SSP).
• Poly-[(trans-1,2-diaminocyclohexane)platinum]-carboxyamylose (POLY-PLAT).
• 4-Hydroxy-sulfonylphenylacetato(trans-1,2-diaminocyclohexane)platinum(II) (SAP).

"What does the future hold for cisplatin and other platinum analogues?"