melphalan and Endometrial-Neoplasms

Fifty consecutive patients with documented advanced or recurrent endometrial carcinoma from 1978 through 1985 were prospectively treated with melphalan, 5-fluorouracil, medroxyprogesterone acetate (MFP) as first-line chemotherapy. From 1987 through 1993, 50 consecutive patients with documented advanced or recurrent endometrial carcinoma were prospectively treated with cisplatin, Adriamycin, etoposide, megestrol acetate (PAV-M) as first-line chemotherapy. Response rates for MFP versus PAV-M, 2- and 5-year survival, median survival, 2- and 5-year progression-free survival, and median progression-free survival were not statistically different. However, there was a significant improvement favoring PAV-M in 2-year (45 versus 14%), 5-year (30 versus 5%), and median survival (22.3 versus 8.7 months) (P = 0.008) compared to MFP in patients with primary advanced endometrial adenocarcinoma. Moreover, there was a significant improvement in 2- and 5-year and median survival (55 and 15% and 26.7 months) for PAV-M compared to MFP (7 and 0% and 7.3 months) (P = 0.002) for the more aggressive other adenocarcinomas (adenosquamous, clear cell, papillary serous, undifferentiated) compared to the more common endometrioid adenocarcinoma. The current data suggest that cisplatin- and adriamycin-based chemotherapy results in some long-term survival benefit for patients with primary advanced endometrial adenocarcinoma and the more aggressive nonendometrioid adenocarcinoma histologies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Endometrial Neoplasms; Etoposide; Female; Fluorouracil; Humans; Medroxyprogesterone Acetate; Megestrol; Megestrol Acetate; Melphalan; Middle Aged; Prospective Studies; Survival Rate

The use of intravenous melphalan at higher doses is limited by severe myelosuppression. It was postulated that GM-CSF would permit the use of higher dose melphalan with only moderate myelosuppression easily manageable in an outpatient setting. Therefore, a phase I study of intravenous melphalan utilizing GM-CSF (recombinant granulocyte-macrophage colony-stimulating factor) support was initiated. Intravenous melphalan at doses of 15-45 mg/m2 was administered every 28 days. GM-CSF was utilized at doses of 10-20 micrograms/kg/day subcutaneously Days 2-21 on a 28-day cycle. Twenty-five patients received 53 courses of therapy. The dose-limiting toxicities were severe or life-threatening granulocytopenia and thrombocytopenia. Utilizing 20 micrograms/kg/day GM-CSF, the maximum tolerated dose (MTD) of melphalan is 30 mg/m2 and, with 10 mg/kg/day GM-CSF, the maximum tolerated melphalan dose is only 20 mg/m2. One patient with ovarian cancer achieved a partial response. Because the reported MTD of intravenous melphalan without GM-CSF is 30 mg/m2, GM-CSF has not allowed sufficient escalation of the intravenous melphalan dose for routine outpatient use.

Topics: Adenocarcinoma; Adult; Agranulocytosis; Anemia; Drug Evaluation; Endometrial Neoplasms; Female; Genital Neoplasms, Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leiomyosarcoma; Melphalan; Ovarian Neoplasms; Recombinant Proteins; Thrombocytopenia

The aim of this study was to determine the efficacy of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for the treatment of endometrial cancer.. Thirty-one patients with stage I-III endometrial cancer were recruited for this study. The stage I patients received only 252Californium neutron intracavitary brachytherapy with a two-channel applicator. The stage II and III patients received both 252Californium neutron intracavitary brachytherapy using a two-channel applicator and parallel-opposed whole pelvic radiotherapy.. The five-year local control rate was 80.6% (25/31), the overall survival rate was 51.6% (16/31), and the disease-free survival rate was 54.8% (17/31). The incidence of serious late complications was 12.9% (4/31).. 252Californium neutron intracavitary brachytherapy using a two-channel applicator combined with external beam radiotherapy was effective for treating endometrial cancer and the incidence of serious late complications related to this combination was within an acceptable range.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Californium; Carmustine; Combined Modality Therapy; Cytarabine; Endometrial Neoplasms; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Podophyllotoxin; Survival Rate; Treatment Outcome

Endometrial cancer is one of the most frequently diagnosed cancer in females with prevalence of 22 in 100,000 women. The etiology of the cancer remains unclear. Despite significant progress towards understanding the patho-mechanism of the disease, effective treatment is still lacking. The results of the study suggest that combined treatment of Ishikawa cells for 24 h with disintegrin and then for 24 h with melphalan severely inhibits important biological functions of the cells. We showed that such strategy have a potent cytotoxic effect. The mechanism of process undergoes probably through inhibition of integrin - dependent signaling. In this study we shown down regulation of Shc and FAK proteins in cells treated with echistatin and melphalan. It suggests that signaling pathways that involve Shc and FAK participation may represent target for antineoplastic strategy. The functional significance of the combined treatment of Ishikwa cells with echistatin and melphalan was found at the level of collagen biosynthesis. Decreased biosynthesis of collagen in extracellular matrix may suppress cell growth and induce apoptosis. The treatment with echistatin and melphalan also showed decreased expression of IGF receptor in comparison to the cells treated with both compounds separately. The data presented suggest that combined therapy with disintegrin - echistatin and alkyalting drug - mephalan may represent a new approach to more effective and safe cancer therapy.

Topics: Cell Line; Cell Line, Tumor; Disintegrins; Endometrial Neoplasms; Humans; Melphalan; Signal Transduction

Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Antineoplastic Agents; Carboplatin; Carrier Proteins; Cisplatin; Colorectal Neoplasms; Cyclophosphamide; DNA Adducts; DNA Damage; DNA Repair; DNA-Binding Proteins; DNA, Neoplasm; Doxorubicin; Drug Resistance, Neoplasm; Endometrial Neoplasms; Etoposide; Female; Fluorouracil; Humans; Melphalan; Methylnitronitrosoguanidine; Mutagenesis; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Paclitaxel; Proto-Oncogene Proteins; Thioguanine; Tumor Cells, Cultured

The ATP bioluminescence assay has demonstrated a strong potential to become a clinical assay for chemosensitivity testing. Currently, chemotherapy of gynecologic cancers remains controversial and empirical. To optimize the patient's chance of survival and to justify related toxicities, the chemoregimen should be individualized and based on the patient's chemosensitivity profiles. This study was performed to identify a panel of active drugs against uterine cancer cell lines for possible use in future chemosensitivity testing. We used the ATP chemosensitivity assays to screen 12 common cytotoxic agents against six uterine cancer cell lines. Drug concentrations required for a 50% surviving fraction were defined as IC50s. When using an IC50 of 0.21 PPC (peak plasma concentration) as a cutoff value for sensitivity, the following 8 drugs were considered effective for uterine cancer cell lines: actinomycin D, Adriamycin, vinblastine, etoposide, 5-fluorouracil, methotrexate, cytosine arabinoside, and mitomycin-C. Meanwhile, 4 drugs, cisplatin, 4OH-Cytoxan, bleomycin, and Alkeran with mean IC50s of 2.1 +/- 0.7, 0.8 +/- 0.1, greater than 5.0, and 0.75 +/- 0.36 PPC, respectively, were considered inactive or partially active with higher IC50s than peak plasma concentrations. In conclusion, the above panel of promising drugs can be further tested in animal models or human cancer specimens for possible use in chemosensitivity testing of uterine cancer patients.

Topics: Adenocarcinoma; Adenosine Triphosphate; Alkaloids; Antineoplastic Agents; Cisplatin; Cyclophosphamide; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Humans; Intercalating Agents; Kinetics; Luminescent Measurements; Melphalan; Mitomycin; Tumor Cells, Cultured; Uterine Neoplasms