Osteosarcoma treatment

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. 

Meanwhile, some phase 2 trials have already been performed on some naturally cancerous dogs, bearing tumors which are histologically close to the corresponding human ones, namely, osteolytic osteosarcomas and fibrosarcomas (bone cancers). Let us give some details about the protocol of treatment we used in the case of a dog weighing 70 kg and suffering from an acute osteolytic osteosarcoma (expected survival time less than 2 weeks on March 26, 1981). 

Four other dogs were treated with SOAz and cured in the same way. This brings real hope for the clinical treatment of osteosarcoma-bearing patients, especially as there is no chemotherapy available at all for such tumors and that surgery (amputation) is the only technique which might be able to delay death. Incidentally, it may be noted that 16,000 men and women died from osteosarcomas in 1980 in E.E.C. countries. . . ... 

Osteosarcoma has recently been diagnosed in a 12-year-old girl. Family history indicates that her paternal aunt died of breast cancer at age 29 after having survived treatment for an adrenocortical carcinoma. An uncle died of a brain tumor at age 38 and the patient s father, age 35, has leukemia. 

The approach to PNET is similar to that described for osteosarcomas, although the chosen cytotoxic agents are different and radiotherapy plays a more important role. Treatment should be started with chemotherapy, usually comprising a combination of agents such as doxorubicin, VP-16, ifosfamide or cyclophosphamide, actinomycin-D and vincristine. After an optimal local response has been obtained, either surgery or local radiotherapy is applied depending on the site of the disease and the applicability of the technique. Sometimes a combination of both is applied. After optimal local treatment. 

Adjuvant chemotherapy involves the use of antineoplastic drugs when surgery or radiation therapy has eradicated the primary tumor but historical experience with similar patients indicates a high risk of relapse due to micrometastases. Adjuvant chemotherapy should employ drugs that are known to be effective in the treatment of advanced stages of the particular tumor being treated. Adjuvant chemotherapy has played a major role in the cure of several types of childhood cancers as well as breast cancer, colorectal cancer, and osteosarcoma in adults. 

Parathyroid hormone has potent anabolic effects on the skeleton if given intermittently being used in clinical trials. Initial concerns about the development of osteosarcoma in rats after prolonged treatment with high doses of parathyroid hormone have not been confirmed in human trials, but surveillance continues (8). In one study there was a mild increase in creatinine, which was thought not to have clinical significance (9). Mild nausea (10) and arthralgia (10,11) have also been reported. 

Very little work has been reported on the role of oxidative stress in osteoblasts. However, osteoblasts can be induced to produce intracellular ROS (Cortizo et al., 2000 Liu et al., 1999), which can cause a decrease in alkalinephosphatase (ALP) activity that is partially inhibited by vitamin E and cause cell death (Cortizo et al., 2000 Liu et al., 1999). Treatment of rat osteosarcoma ROS 17/2.8 cells with tumor necrosis factor-alpha (TNF-a) suppressed bone sialoprotein (BSP) gene transcription through a tyrosine kinase-dependent pathway that generates ROS (Samoto et al., 2002). H202 modulated intracellular calcium (Ca2+) activity in osteoblasts by increasing Ca2+ release from the intracellular Ca2+ stores (Nam et al., 2002). 

Two carcinogenicity bioassays were conducted in rats (3-60x MRHD). Treatment resulted in a marked dose-related increase in the incidence of osteosarcoma, a rare mahgnant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40-50% in the high-dose groups. Teriparatide also caused a dose-related increase in osteoblastoma and osteoma in both sexes. Bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia Second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age (at 3x to 20x MRHD based on body surface area). The... 

In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a mahgnant bone tumor) that was dependent on dose and treatment duration. Effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20 meg dose. 

The current label for PTH(l-34), the first approved PTH analogue, reports dose-related increase in osteosarcomas, osteoblastomas, and osteomas in two-rat carcinogenicity studies as well as results from a second two-year study in rats designed to determine the effect of treatment duration and animal... 

Methotrexate is a folic acid antagonist that inhibits the enzyme dihydrofolate reductase. This agent is mainly used in the treatment of both cancer [trophoblastic neoplasms, leukemias, breast carcinoma, carcinoma of gastric, esophagus, testes, lymphomas] and non-cancer diseases [psoriasis rheumatoid arthritis]. Recent successful results using high-dose [>lg/ m ] methotrexate followed by leucoverin in the treatment of head and neck carcinomas and osteosarcoma has led to a more widespread use of this therapy in patients with these and other tumors. 

Human osteoblasts like cells osteosarcoma SaOS-2 cells were cultured for 24 hours, after which varying doses of a water dispersible microemulsion preparation of lycopene or vehicle of the same dilution were added. The cells were further cultured for 24 to 144 h and the cell numbers were counted. Lycopene at 10 and 10 M had significant stimulatory effects on cell numbers, compared with the corresponding vehicle treatment, at all time points from 24 h to 144 h. The effects of lycopene on activity of the differentiation marker alkaline phosphatase activity in the absence or presence of dexamethasone were shown to be dependent on osteoblasts of human origin [79]. 

Far fewer studies to date have looked at the role of LRP in clinical drug resistance. LRP has been shown to have prognostic significance in AML and epithelial ovarian cancer (23). In the latter study, LRP was an independent determinant of response to treatment and overall survival, whereas Pgp and MRP were not. LRP levels were also shown to be increased post-chemotherapy in osteosarcoma and this was a poor prognostic sign (27). LRP levels prior to chemotherapy did not show prognostic significance. 

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