Anti-tumour activity

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

A resurgence of interest in these seemingly simple complexes of platinum started in 1969 when B. Rosenberg and co-workers discovered the anti-tumour activity of cis-[PtCl2(NH3)2]... 

Curdlan possesses anti-tumour activity similar to that shown by fungal (1-D-glucans, a property which appears to be related to the ability to form triple helices. 

Again both S- and O-bonded sulphoxides are found. mer-[RuCl3(Ph2SO)3] has one S-bonded sulphoxide and two O-bonded sulphoxides (one trans to Cl, one trans to S) [112], The imidazole-substituted complexes are being studied as possible radiosensitizers and for anti-tumour activity. 

The relatively recent discovery that ds-Pt(NH3)2Cl2 possesses significant anti-tumour activity while the trans-isomer is inactive has made distinguishing the isomers of greater importance. 

When solutions containing the aqua complexes derived from cisplatin react with pyrimidines and other bases and are exposed to air, blue solutions (and solids) result [94], These are mixed-valence oligomers (n = 4). Some have anti-tumour activity but have not yet found clinical use. 

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.

The compound Au(dmamp)(02CMe)2 (dmamp = 2-Me2NC6H4) displays some anti-tumour activity and is undergoing tests on its anti-bacterial activity [200]. 

As endothelins mediate potent vasoconstrictor effects, ECE inhibitors and endothelin receptor antagonists were developed for the treatment of cardiovascular diseases, such as acute and chronic heart failure, pulmonary hypertension and subarachnoid haemorrhage. As ETa recqrtors have potent mitogenic responses and may promote progression of ovarian and prostate cancer and bone metastases ETA receptors are also considered as a potential targets for anti-tumour activity. 

Oxidation of the phenol ring of cannabidiol (73) or cannabinol to a qui-none ring has been shown to afford compounds with anti-tumour activity. However, these compounds do not bind to the CBi receptor and their mechanism of action is unclear [128],... 

We shall now describe the chemistry of those inorganic complexes which are known to have anti-tumour activity in an effort to outline the permutations which such molecules permit and to indicate possible functional modes. We start from the basic observation of Rosenberg (1).Cis [PtCl2 (NH8)d is a very effective anti-tumour drug. Compounds related to it such as trans [PtCl2(NH3)2] are ineffective. Out of a wide range of transition metal complexes tested few have proved to be effective. The successful compounds have certain common features which can be used to circumscribe some of the factors which are probably required for such a drug. 

Optical activity in metal complexes may also arise either if one of the ligands bound to the metal in the first co-ordination sphere is itself optically active or if the complex as a whole lacks a centre of inversion and a plane of symmetry. Thus all octahedral cts-complexes of the tris-or bis-chelate type have two isomeric forms related by a mirror plane, the d- and /-forms. These species have circular dichroism spectra of identical intensities but opposite in sign. The bands in the circular dichroism spectrum are, of course, modified if ligand exchange occurs but they are also exceedingly sensitive to the environment beyond the first co-ordination sphere. This effect has been used to obtain association constants for ion-pair formation. There also exists the possibility that, if such compounds display anti-tumour activity, only one of the mirror isomers will be effective. 

Modifying lymphocytes in order to enhance their anti-tumour activity Modifying tumour cells to enhance their immunogenicity Inserting tumour suppressor genes into tumour cells... 

Deoxoartemisinin and carboxypropyldeoxoartimisinin have also been shown to have anti-tumour activity and, NMR studies on solution conformations have been reported <00BBR359>. One of the problems with artemisinin use is its poor water solubility characteristics. An attempt to rectify this, and to overcome stability problems associated with sodium artesunate in solution, has involved the introduction of amino group functionality as in 127 (eg. R = 0(CH2)3NR r2 where NR r2 = morpholine). The maleate salt of this compound has reasonable water solubility and aqueous solutions are stable at room temperature for an extended time. However activity against Plasmodium knowlesi in rhesus monkeys after oral administration was poorer compared with artesunic acid <00JMC1635>. 

Figure 20.2 Mechanism of the anti-tumour activity of cisplatin. (From Brabec and Kasparkova, 2005. Reproduced with permission from John Wiley Sons., Inc.)...

Erba E, Bergamaschi D, Ronzoni S, Faretta M, Tavema S, Bonfanti M, et al. Mode of action of thiocoraline, a natural marine compound with anti-tumour activity. Br. J. Cancer. 1999 Jun 80(7) 971-80. 

One of the first biological activities for which sesquiterpene lactones were screened was their possible anti-tumour activity. Studies have shown that... 

Figure 1.3. Structure of PKl (HPMA copolymer doxorubicin), a 28-kDa polymeric carrier-drug conjugate investigated for its anti-tumour activity in a phase I clinical study. Adapted from reference [15].

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

Liposome-encapsulated immunomodulators are currently under investigation in different patient groups although this development has certainly not advanced as far as that with the liposomal anthracyclines. MLV-MTP-PE (multilamellar vesicles-muramyl tripeptide-phos-phatidylethanolamine) was studied in several clinical trials in osteosarcoma patients who developed pulmonary metastases during adjuvant chemotherapy [108], The intravenous administration of MLV-MTP-PE induced tumouricidal properties in monocytes as well as increase in serum IL-1 shortly after intravenous infusion. Furthermore elevations in C-reactive protein, 32-microglobulin and ceruloplasmin were frequently observed. Even higher anti-tumour activity was observed in combination with ifosfamide. These preliminary results suggests that liposome-encapsulated immunomodulators in combination with chemotherapy may be an appropriate treatment for recurrent disease. 

Resistance to tamoxifen is a complex phenomenon and there is evidence that relapse under tamoxifen therapy is linked to the estrogenicity of the drug. Both, the great success of tamoxifen and its liabilities have boosted the search for new analogues in the past 25 years with the goal of identifying a compoimd with increased anti-tumour activity and with reduced side effects. A second generation of structurally related triphenyl-ethylenes like... 

Roos IA, Arnold M. Interaction of an anti-tumour active platinum complex with DNA. J ClinHematol... 

Gallo D, Ferlini C, Distefano M, et al. Anti-tumour activity of a panel of taxanes toward a cellular model of human cervical cancer. Cancer Chemother Pharmacol 2000 45(2) 127-132. 

Terpenes are polymers of the 5-carbon compound isoprene (Figure 1.12) and, as such, generally display properties similar to those of hydrocarbons. Terpenoids are substituted terpenes (i.e. contain additional chemical groups, such as an alcohol, phenols, aldehydes, ketones, etc.). Only a few such substances could be regarded as true drugs. Terpenes, such as limonene, menthol and camphor, form components of various essential oils with pseudo-pharmaceutical uses. A number of these molecules, however, exhibit anti-tumour activity, of which taxol is by far the most important. 

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