Cisplatin also clinical activity

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

The most important clinical use of vinblastine is with bleomycin and cisplatin (see below) in the curative therapy of metastatic testicular tumors, although it has been supplanted by etoposide or ifosfamide in this disease. It is a component of the standard curative AB VD regimen for Hodgkin s disease (adriamycin, bleomycin, vinblastine, and dacarbazine). It also is active in Kaposi s sarcoma, neuroblastoma, and histiocytosis X, and in carcinoma of the breast and choriocarcinoma. 

Metallothionein is also induced by a variety of nonmetals, and exposure to these agents often can cause tesistance to anticancer drugs such as cisplatin (Basu and Lazo 1991). Expression of v mos can attenuate the glucocorticoid-induced metallothionein expression and cisplatin resistance. Transcriptional activation of c-Ha-ras oncogene expression in murine NIH 3T3 cells with dexamethasone produces an increase in metallothionein content and a decrease in cisplatin accumulation (Isonishi et al. 1991). The ability of dexamethasone to affect the sensitivity of cells to electrophilic antineoplastic agents could be of some clinical interest because of its frequent usage as an antiemetic. 

Dimeric complexes like [Cl(NH3)Pt H2N(CH2)4NH2 Pt(NH3)Cl]Cl2 are also being investigated as they bind to DNA in a different way to that involved in cisplatin binding and are active in cisplatin-resistant human tumour cells. They are more potent than cisplatin in lung cancer models in vivo and are likely to go on clinical trials in the near future [204],... 

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

The chemotherapeutic agent d.v-diammincdichloroplatinum(II), cis-DDP, or cisplatin, can form covalent adducts with many cellular macromolecules, but there is convincing evidence that its cytotoxic properties are a consequence of bifunctional-DNA adduct formation [ 1 ] [2]. Platinum binds to the N(7) position of purine nucleotides, resulting predominantly in 1,2-d(GpG) and l,2-d(ApG) intrastrand cross-links, but also in l,3-d(GpNpG) intrastrand, interstrand and protein-DNA cross-links [3][4], The 1,2-intrastrand cross-links, which comprise 90% of the DNA adducts, are not formed by the clinically inactive trans-DDP because of geometric constraints, and attention has therefore focused on these adducts as the active lesions in the anticancer activity of the drug. 

Cisplatin was found to be outstandingly active against testicular and ovarian cancers, and also to exhibit useful clinical efficacy in head and neck, bladder and lung cancers. Over the years, it has become one of the most broadly used cytotoxic agents. Unfortunately, the outstanding antitumor effect is accompanied by dose-limiting, frequently lethal, nephrotoxicity (Tab. 16.2). 

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