2KPF 6
1.5 Drug Discoveries
1.5.1 Cisplatin
This compound was first described in 1845225, but its anticancer properties were only discovered in 1964. It has been found that cisplatin is able to enter cells by passive diffusion226 and also in a different manner, as more recently discovered, by active transport mediated by the copper transporter, Ctr1p227,228, in yeast and mammals. The cytotoxicity of cisplatin has been shown to be due to its cross-linking binding to DNA that interferes with replication and transcription, in turn causing cell death.203
Cisplatin (Figure 1.4), marketed as Platinol®, showed incredible success by providing the first cure for small cell lung cancer and improving survival of patients with ovarian cancer in the advanced stages. It was also used for bladder, neck and head cancers and cured 80% of patients with testicular cancer.229 Unfortunately, side effects and drug resistance started to limit cisplatin‟s clinical applications. Biological carriers were then added to cisplatin to increase specificity which subsequently reduced side effects and drug resistance. Other drugs that are more effective with less toxic side effects, and possibly more favourable properties such as solubility in aqueous solution, were therefore required. Therefore since the early 1970s more than 3000 platinum complexes have been synthesised and tested.230
Figure 1.4: The structure of the dimethylformamide solvate of cis-diaminedichloroplatinum(II),231 known as cisplatin (hydrogen atoms have been excluded for clarity).
1.5.2 Platinum-based Drugs
Even minor modifications to the structure of drugs can have an impact on their biological character including their antitumour activity and toxicity. Thus research efforts for platinum complexes that might produce more specific anticancer drugs with a broader range of antitumour activity have been investigated. Subsequently, a few more platinum- based drugs have been accepted by the Food and Drug Administration (FDA)232: Carboplatin (ovarian cancer)233, Satraplatin (hormone-refractory prostate cancer)234, Oxaliplatin (metastatic colorectal cancer)235, and Picoplatin (small-cell lung cancer)236 (Figure 1.5). Side effects have also been noted for some of these drugs: suppression of bone marrow activity by Carboplatin and peripheral nerve damage by Oxaliplatin.237
NH3+ N
H3 + Pt O
O O
O
Cl O NH2+
O Cl
N H3
+
Pt O 4-
O
N H2+
N H2
+ Pt
2-
O
O O
O
Cl Cl N
H3 + N+ Pt
2-
Figure 1.5: Some of the platinum-based drugs accepted by the Food and Drug Administration (FDA)232 for clinical use in treating cancer.
1.5.3 Examples of Other Cancer Drugs
238,239Methotrexate, marketed as Trexall™ (originally approved by FDA on 21 March 2001) is an antimetabolite used to treat epidermoid cancers of the head and neck, breast cancer and lung cancer (particularly squamous and small cell). It operates by competitive inhibition of folic acid reductase to interfere with DNA synthesis, repair and replication.
Carac® (originally approved by FDA on 27 October 2000) contains fluorouracil which is an antimetabolite and obstructs the methylation reaction of deoxyuridylic acid to thymidylic acid. It has found use on the skin treating pre-cancerous and cancerous skin growths.
Hydrea® (originally approved by FDA on 7 December 1967) is an antineoplastic agent, Carboplatin Satraplatin Oxaliplatin Picoplatin
affects cancer cells or sickled red blood cells in the body. It has been used to treat melanoma, primary squamous cell (epidermoid) carcinomas of the head and neck, chronic myelocytic leukemia and recurrent, metastatic, or inoperable carcinoma of the ovary.
Mercaptopurine is in a cancer medication sold as Purinethol™ (originally approved by FDA on 11 September 1953) and is also an antimetabolite. It inhibits the biosynthesis of adenine nucleotides and has been used to treat acute lymphatic leukemia or acute myelogenous leukemia.
Cerubidine® (originally approved by FDA on 3 February 1995) has antimitotic and cytotoxic activity owing to a number of proposed mechanisms of action, including inhibiting topoisomerase II. Its active ingredient is daunorubicin hydrochloride and it has shown an antitumour effect against a range of animal tumours.
Doxorubicin hydrochloride is the active ingredient in Doxil® (originally approved by FDA on 17 November 1995). It is an anthracycline topoisomerase inhibitor indicated for patients with ovarian cancer, where the disease has advanced or recurred after platinum- based chemotherapy.
Taxol® (originally approved by FDA on 29 December 1992) contains pacitaxel which is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. It has been indicated as initial and ensuing therapy for the treatment of advanced carcinoma of the ovary, as well as breast cancer. In combination with cisplatin it has been used to treat non-small cell lung cancer.
Mitomycin® (originally approved by FDA on 19 April 1995) has an active ingredient of the same name. It is not recommended as a single-agent, but has shown usefulness in conjunction with other chemotherapeutic drugs in treating disseminated adenocarcinoma. It is a potent DNA cross-linker and has also been used for breast, oesophageal and bladder cancers.
Carmustine is the active ingredient in Gliadel® (originally approved by FDA on 23 September 1996), which is a nitrosourea oncolytic agent. It has been indicated for brain
tumours; producing an antineoplastic effect by alkylating DNA and RNA. It also found use in treating newly-diagnosed high grade malignant glioma and recurrent glioblastoma multiforme.
Camptosar® (originally approved by FDA on 14 June 1996) contains irintecan which is a derivative of cemptothecin. Its cytotoxicity has been shown to be caused by double- strand DNA damage created during DNA synthesis when replication enzymes interact with the ternary complex. This drug has found use for metastatic carcinoma of the colon or rectum; either as combination first-line therapy or when the disease has recurred or progressed.
Recently, the discovery that a metal compound does not have to be extremely cytotoxic to have effective anti-cancer properties was made. Some promising discoveries have been made for the metals gallium240 and ruthenium241 (which have mainly anti-metastatic effects – prevent the spreading of cancers or are discriminatory for metastases), as well as for gold242 (Figure 1.6).
Even though some complexes have successfully been through Phase I and II human clinical trials, the mechanisms of their action are still often (but not always) unknown. The combination of different drugs that have varying modes of action often synergises their effects. Thus there is continued interest in the various metallopharmaceutical mechanisms due to the anticipation that together they might provide an even wider range of successful chemotherapeutic agents.243
O O+
O O +
Ga
O O 6-
O +
O
O
N + N+
O O
Ga O 6-
N
+ Au
3-N+ N
N +
N
Au 3-N+ N
N +
N
Figure 1.6: Structures of oral gallium complexes240 (left) and gold(III)–porphyrin complexes242 (right) that have been used for cancer treatment.