Cisplatin sarcomas

Am(m)ine and pyridine complexes such as mer-[RhCl3(NH3)3] (45) were the first rhodium(III) complexes to be tested because they contain cis-chloride ligands as does cisplatin (213). Complex 45 displays a positive dose-response relationship against several tumor cells such as Sarcoma 180. 

This is an unusual drug in that it contains a metal atom, platinum (Pt) in this case. Cisplatin reacts with DNA to cross-link bases, disrupting normal DNA structure and function. This agent has found broad use in cancer chemotherapy, including efficacy in tumors of the testis, ovary, bladder, head and neck, thyroid, cervix, and endometrium. It is also active against neuroblastoma and osteogenic sarcoma. 

These studies were followed by others that demonstrated the potential for therapeutic enhancement by combined cisplatin-radiation treatments with primary murine bladder cancer (60), EMT-6 mammary tumors and KHT and RIF-1 sarcomas (61), and Lewis lung carcinoma (62). 

Topotecan (Hycamtin) [Antineoplastic] WARNING Chemo precautions, for use by healthcare provides familiar w/ chemo agents, BM suppression possible Uses Ovarian CA (cisplatin-refractory), CCTvical Ca, NSCLC, sarcoma, ped NSCLC Action Topoisom ase I inhibitor -1- DNA S5mth Dose 1.5 mg/mVd as a 1-h IV inf X 5 d, r eat q3wk -1- w/ renal impair Caution [D, —]... 

After that, tests were undertaken to study the growth-reducing capacity of cisplatin on animal tumors, such as Sarcoma 180 in Swiss white mice13. The results were so positive - in many cases total regression of the tumors was observed - that clinical trials were soon thereafter planned and performed. The first studies, in 1972, demonstrated remarkable anti tumor activity14 for cisplatin. However, large-scale applications had to... 

Osteogenic Sarcoma. Cisplatin figures prominently in the treatment of primary bone sarcomas. Single-agent response rates approximate 30% in... 

Endometrial Ewing s sarcomao" Gastric Head and neck,squamous cell Islet cell (pancreas) Kaposi s sarcoma Doxorubicin cisplatin + cyclophosphamide CAV Cyclophosphamide (or Ifosfamide) + doxorubicin (Adriamycin) + vincristine CF epirubidri + cisplatin 5-fluorouraci1 Cisplatin + S-fluorouracil Methotrexate Screptozotocin + S-fluorouracil Etoposide or interferon affa or vinblastine ABV doxorubicin (Adriamycin) + bteomycin + vincristine or vinblastine... 

Ifosfamide is an alkylating agent belonging to the group of oxazaphosphorines. It is used to treat a variety of solid tumors in children, including rhabdomyosarcoma, soft tissue sarcomas, Wilms tumor, bone sarcomas, and neuroblastoma, and leukemias and lymphomas in adults. It is also sometimes used in combination with other drugs, such as doxorubicin or cisplatin and etoposide. 

Mune T, Yasuda K, Ishii M, Matsunaga T, Miura K. Tetany due to hypomagnesemia induced by cisplatin and doxorubicin treatment for synovial sarcoma. Intern Med 1993 32(5) 434-7. 

Current opinion concerning the mechanism of delivery of liposomal therapeutics to tumors is that, once in the tumor, standard liposomes are localized in the extra-cellular fluid that surrounds the tumor cell but do not enter it i 8 ii Therefore, for delivery of the therapeutic agent, the drug must first be released into the extra-cellular fluid, from where it must then diffuse into the cell. There is the evidence that doxorubicin is released efficiently from Doxil liposomes, to be taken up by the cell in ovarian cancer and Kaposi s sarcoma. Concentrations of doxorubicin achieved in cells have been estimated as up to 13 times higher from Stealth liposomes than with a simple doxorubicin injection in patients undergoing treatment of Kaposi s sarcoma. hi contrast, evidence from the use of cisplatin seems less definitive. In studies comparing Stealth liposomal cisplatin (SPl-077) with standard cisplatin in... 

Cisplatin is strongly inhibitory to many other tumours of rats and mice [43] and is not schedule-dependent, since a single dose day 1 after tumour implantation, or daily injection for 9 days, are equally effective on L-1210 [44]. Recently the M-5076 sarcoma has been shown to have an interesting pattern of response to cisplatin and selected analogues, suggesting its utility as a screen for these agents [45]. 

Photographic demonstration of the dramatic ability of cisplatin to cure a Sarcoma-180 murine tumor (reproduced by permission from Reference 47). 

DDP or cisplatin), a classic coordination complex, the synthesis and structure of which were known for more than a century (80, 133). Subsequent investigations of the effects of c -DDP on rapidly dividing mammalian tumor cells indicated significant antitumor activity against sarcoma 180 and leukemia L1210 in mice (110). Clinical trials commenced soon thereafter and in 1979 cisplatin was approved by the FDA for the treatment of several human cancers. 

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. 

Etoposide is used primarily for treatment of testicular tumors, in combination with bleomycin and cisplatin, and in combination with cisplatin and ifosfamide for small cell carcinoma of the lung. It also is active against non-Hodgkin s lymphomas, acute nonlymphocytic leukemia, and Kaposi s sarcoma associated with AIDS. Etoposide has a favorable toxicity profile for dose escalation in that its primary acute toxicity is myelosuppression. In combination with ifosfamide and carboplatin, it is frequently used for high-dose chemotherapy in total doses of 1500-2000 mg/nf. 

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