Doxorubicin ovarian cancer

Liposomal doxorubicin is an irritant, not a vesicant, and is dosed differently from doxorubicin, so clinicians need to be very careful when prescribing these two drugs. The pharmacokinetics of liposomal doxorubicin are best described by a two-compartment model, with a terminal half-life of 30 to 90 hours.20 Liposomal doxorubicin has shown significant activity in the treatment of breast and ovarian cancer, along with multiple myeloma and Kaposi s sarcoma. Side effects include mucositis, myelosuppression, alopecia, and palmar-plantar erythrodysesthesia. The liposomal doxorubicin may be less cardiotoxic than doxorubicin. 

Campos SM, Penson RT, Mays AR, et al. The clinical utility of liposomal doxorubicin in recurrent ovarian cancer. Gynecol Oncol 2001 81 206. 

Gordon AN, Granai CO, Rose PG, et al. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000 18 3093. 

In September 2007, the EMEA approved the use of trabectidin against ovarian cancer (OC) and STS. In November 2009, Yondelis received its second marketing authorization from the European Commission for its administration in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer presently, trabectedin (36) is under Phase II trials for the treatment of paediatric sarcomas as well as breast and prostate cancers. The European Commission and the US Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and... 

Doxorubicin and dannorabicin are antibiotics made from microorganisms of the family Streptomyces peucetius. The stmcture of these anthracyclines contains an aminosaccarhide residue daunozamine attached to a naphthacenequinone nucleus. Doxorubicin differs from daunorubicin in the presence of a hydroxyl gronp at C14. A nnmber of mechanisms have been suggested in which anthracyclines exhibit cytotoxicity. They canse DNA to denature, are involved in oxidation-rednction reactions, chelate bivalent cations and react with cell membranes, changing their fnnction. They are used for severe leukemia, lymphoma, breast and ovarian cancer, and other solid tumors. 

Kaye SB, Lubinski J, Matulonis U et al (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCAI or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30 372-379... 

G. Other applications Herceptin has been combined with cisplatin in the treatment of heavily pretreated metastatic breast cancer. Treatment of patients with ovarian cancer is under investigation. A recent study demonstrated that Herceptin increased the clinical benefits of first-line chemotherapy—doxorubicin (or epiru-bicin) and cyclophosphamide or pacli-taxel—in metastatic breast cancer that overexpressed HER2. 

Investigators found that human breast cancer cell lines with BRCAl mutations showed a twofold to fourfold increase in apoptosis after treatment with ionizing radiation, cisplatin, or doxorubicin, compared with cells free of mutations. They also found that BRCAl tumor cell lines were resistant to other agents, such as paclitaxel (Taxol) and docetaxel (Taxotere), treatments used commonly in ovarian cancer and advanced-stage breast cancers. 

Hence women with BRCAimutations who develop breast or ovarian cancer may not be good candidates for treatment with certain types of chemotherapy agents such as Taxol. Doxorubicin, cisplatin, or other newly discovered agents might be a better choice. In the future, genetic profiling may point the way to optimal treatment of cancer. 

Doxorubicin Oxygen free radicals bind to DNA causing single- and double-strand DNA breaks inhibits topoisomerase II intercalates into DNA Breast cancer, Hodgkin s and non-Hodgkin s lymphoma, soft tissue sarcoma, ovarian cancer, non-small cell and small cell lung cancer, thyroid cancer, Wilms tumor, neuroblastoma Nausea, red urine (not hematuria) Cardiotoxicity (see text), alopecia, myelosuppression, stomatitis... 

Compared to other solid tumors, ovarian cancer is relatively responsive to chemotherapy, but unlike testicular cancer, cure is not common for patients with advanced disease. Prior to the incorporation of cisplatin or carboplatin into treatment regimens, chemotherapy for advanced-stage ovarian cancer consisted of combinations of alkylating agents and doxorubicin. Response rates from such regimens were of the order of 33-65%, and fewer than 10% of patients survived 5 years [51]. 

Doxorubicin Mycet Doxil/Caelyx Breast cancer Sarcoma, ovarian cancer, breast cancer... 

Chemotherapy refers to drug administration with highly serious side effects, such as nausea, hand and foot rashes, mouth sores, and increased risk of infection, easy bruising, and so on. Therefore, liposomal carriers have been used in order to improve the drug s biodistribution and protect the patient from those side effects. The main anticancer drugs used to treat ovarian cancer are carboplatin and cisplatin, paclitaxel, topotecan, and lurtotecan. PEGylated liposomal doxorubicin has been approved as a regimen for patients with metastatic ovarian cancer refractory to both paclitaxel and platinum based-therapy [449],... 

A variety of new molecules either in combination with liposomal doxorubicin or not are in development at the moment [457]. For example, a phase III study will be conducted to test the efficacy and safety of pattupilone versus PEG-liposomal DXR in taxane/platinum refractory/resistant patients with recurrent epithelial ovarian, primary fallopian, or primary peritoneal cancer. A phase III randomized study of Telcyta with Doxil/Caelyx versus Doxil/Caelyx has been planned in patients with platinum-refractory or platinum-resistant ovarian cancer. A phase II study relevant to side effects and best dose of ixabepilone combined with liposomal DXR will be assessed in patients with advanced ovarian epithelial, peritoneal cavity, or fallopian tube cancer or metastatic breast cancer. 

Rose, P (2005), Pegylated liposomal doxorubicin Optimizing the dosing schedule in ovarian cancer, Oncologist, 10,205-214. 

Tambaro, R., Greggi, S., Iaffaioli, R. V., Rossi, A., Pisano, C., Manzione, L., Ferrari, E., Di Maio, M., Iodice, F., Casella, G., Laurelli, G., and Pignata, S. (2003), An escalating dose finding study of liposomal doxorubicin and vinorelbine for the treatment of refractory or resistant epithelial ovarian cancer,Ann. Oncol., 14,1406-1411. 

Verhaar-Langereis, M., Karakus, A., van Eijkeren, M., Voest, E., and Witteveen, E. (2006), Phase II study of the combination of pegylated liposomal doxorubicin and topo-tecan in platinum-resistant ovarian cancer, Int. J. Gynecol. Cancer, 16, 65-70. 

Doxorubicin Doxil/Caelyx MPEG-DSPE, HSPC, cholesterol, ammonium sulfate, sucrose, histidine Refractory Kaposi s sarcoma ovarian cancer recurrent breast cancer Alza/SP Europe... 

Most of the important antitumor compounds used for chemotherapy of tumors are microbially-produced antibiotics. These include actinomycin D, mitomycin, bleomycins and the anthracyclines, daunorubicin and doxorubicin. The recent successful molecule, taxol (=paclitaxel), was discovered in plants but also is a fungal metabolite. It is approved for breast and ovarian cancer and is the only antitumor drug known to act by blocking depolymerization of microtubules. In addition, taxol promotes tubulin polymerization and inhibits rapidly dividing mammalian cancer cells. It also inhibits fungi such as Pythium, Phytopthora and Aphanomyces spp. by the same mechanism. ... 

A syndrome of palmar-plantar erythema (progressing in some patients to blistering and desquamation) has been reported in seven of eight patients with advanced breast or ovarian cancer who received high-dose doxorubicin (125-150 mg/m ) (79). By contrast, in a similar dose intensification study in which patients received epirubicin 200 mg/m with cyclophosphamide and growth factor support, the pal-mar-plantar syndrome did not occur (80). 

Bronchud MH, Howell A, Crowther D, Hopwood P, Souza L, Dexter TM. The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer 1989 60(l) 121-5. 

Muggia FM, Hainsworth JD, Jeffers S, Miller P, Groshen S, Tan M, Roman L, Uziely B, Muderspach L, Garcia A, Burnett A, Greco FA, Morrow CP, Paradise LJ, Liang LJ. Phase II study of liposomal doxorubicin in refractory ovarian cancer antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997 15(3) 987-93. 

The mode of action of mitoxantronc involves intercalation and inhibition of topoisomcrasc 11. In contrast to doxorubicin. it docs not undergo redox cycling to form oxygen free radicals, because iLs redox potential is outside the reductive capability of mammalian reductases. Mitoxantrone is approved for remission-induction therapy in acute nonlympho-cytic leukemia, where it typically is used with cytarabine. It also is active against other leukemias, breast cancer, and ovarian cancer. The dose-limiting toxic effect is myelosup-... 

Doxorubicin-resistant tumors Eungal infections Lymphomatous meningitis Metastatic malignant uveal melanoma Ovarian cancer Advanced cancer Various tumors Advanced cancer... 

PEGylated liposomal doxorubicin (DOXIL /Caelyx ) was the first and is still the only stealth liposome formulation to be approved in both USA and Europe for treatment of Kaposi s sarcoma (67) and recurrent ovarian cancer (68, 69). Currently, (DOXIL /Caelyx ) is undergoing trials for treatment of other malignancies such as multiple myelomas (70), breast cancer (71, 72), and recurrent high-grade glioma (73). 

Thigpen JT et al (2005) Role of pegylated liposomal doxorubicin in ovarian cancer. Gynecol Oncol 96 10-18... 

Perez-Lopez ME, Curiel T, Gomez IG, forge M (2007) Role of pegylated liposomal doxorubicin (Caelyx) in the treatment of relapsing ovarian cancer. Anticancer Drugs 18 611-617... 

The second discovery that enabled liposomes to be developed into efficacious anticancer drug delivery systems was the development of an efficient loading procedure that resulted in liposomes with high drug concentrations. This in turn permitted a reduction in the amount of phospholipid to be administered concomitantly with a given drug dose. This advanced technique was developed during formulation studies on doxorubicin that eventually led to a liposomal formulation that is now licensed as Caelyx for the treatment of Kaposi s sarcoma and ovarian cancer. 

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... 

Muggia, E. M., Hainsworth, J. D., Jeffers, S., Miller, R, Groshan, S., Tan, M., Roman, L., Uziely, B., Muderspach, L., Garcia, A., Burnett, A., Greco, E A. Phase 11 study of liposomal doxorubicin unrefractory ovarian cancer anti-tumor activity and toxicity modification by liposomal encapsulation. J. Clin. Oncol. 1997, 75, 987—993. 

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