Melphalan for the Treatment of Patients With Recurrent Epithelial Ovarian Cancer

Davis-Perry, Shonda; Hernández, Enrique; Houck, Karen; Shank, Rachel

doi:10.1097/01.coc.0000027269.06091.e9

Cited by 10 publications

(6 citation statements)

References 17 publications

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“…The toxicity profile did not differ greatly from that reported after a 1-h infusion (9) and was acceptable in such a heavily pretreated patient population. However, the thrombocytopenia reported in this study seemed not to be as significant as that reported by Davis-Perry et al after repeated oral administration of 7 mg/m 2 melphalan for 5 successive days (42). Indeed, these authors reported that grade I thrombocytopenia occurred in 19.7% of courses, grade II in 1.4% of courses and grade III in 5.6% of courses.…”

Section: Discussioncontrasting

confidence: 48%

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Phase II study of melphalan as a single-agent infused over a 24-hour period with individual adapted dosing in patients with recurrent epithelial ovarian cancer

Mougenot

Fabbro²,

Bressolle³

et al. 2006

Oncol Rep

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Abstract. The current study was performed to evaluate the efficacy and toxicity of a chemotherapy treatment using melphalan administered over a 24-h period with individual adapted dosing in advanced ovarian cancer. Melphalan was infused intravenously with an automatic infusion pump over a 24-h period. The schedule was repeated every 28 days for a maximum of 6 cycles. The initial administered dose was 25 mg/m 2 . Drug adjustment was then made using a population approach, with the aim of constraining the overall area under the plasma concentration-time curve within 2.0-2.5 mg • h/l. A total of 96 courses of chemotherapy was administered. The toxicity profile did not differ greatly from that reported after a 1-h infusion and was acceptable in such a heavily pretreated patient population. Twenty-five patients were assessable for response and survival. Four (16%) partial responses were observed, which lasted 9, 10, 13 and 37 months, respectively. Three patients experienced stable disease during 8, 14 and 22 months, respectively. The 1-and 2-year survival rates were 18% and 6%, respectively. At the time of analysis, two patients remained alive with progressive disease at 22 and 37 months, respectively. In conclusion, melphalan administered over a 24-h period in platinum-and taxane-resistant ovarian cancer patients appeared to provide some clinical benefits with manageable toxicity. Based on these results, future studies comparing melphalan administered over a 24-h period and oral melphalan administrations will be scheduled.

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Section: Discussioncontrasting

confidence: 48%

“…Indeed, these authors reported that grade I thrombocytopenia occurred in 19.7% of courses, grade II in 1.4% of courses and grade III in 5.6% of courses. However, comparable response rates were observed in the present study and a study published by Davis-Perry et al (42).…”

Section: Discussioncontrasting

confidence: 46%

Phase II study of melphalan as a single-agent infused over a 24-hour period with individual adapted dosing in patients with recurrent epithelial ovarian cancer

Mougenot

Fabbro²,

Bressolle³

et al. 2006

Oncol Rep

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“…Melphalan functions by alkylating DNA at the N7 position of the guanine residue and induces DNA inter-strand cross-linkages, leading to the inhibition of DNA and RNA synthesis, and hence inducing cytotoxicity against both dividing and non-dividing tumor cells. Melphalan was identified as a promising therapeutic agent for the treatment of ovarian cancer patients who harbored BRCA1/2 mutations [247][248][249]. In order to tackle the detrimental effect of melphalan, the cancer cells were determined to rewire their metabolic pathway.…”

Section: Chemotherapeutic Drugsmentioning

confidence: 99%

Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence

et al. 2023

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Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer.

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“…Recently it has been suggested as a therapeutic agent in the treatment of a variety of cancers such as ovarian cancer, breast cancer, colorectal cancer, and melanoma . However, its use has been limited due to severe side effects such as bone marrow suppression, leukopenia, and thrombocytopenia, − largely due to lack of selectivity for cancer cells, and so it was selected as the model drug for investigating our approach. A proline dipeptide prodrug of melphalan was designed to follow DPPIV substrate specificity requirements.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase IV as a Potential Target for Selective Prodrug Activation and Chemotherapeutic Action in Cancers

et al. 2014

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The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r2 = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r2 = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI50 = 261 μM) compared to that in SK-MEL-5 cells (GI50 = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

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Melphalan for the Treatment of Patients With Recurrent Epithelial Ovarian Cancer

Cited by 10 publications

References 17 publications

Phase II study of melphalan as a single-agent infused over a 24-hour period with individual adapted dosing in patients with recurrent epithelial ovarian cancer

Phase II study of melphalan as a single-agent infused over a 24-hour period with individual adapted dosing in patients with recurrent epithelial ovarian cancer

Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence

Dipeptidyl Peptidase IV as a Potential Target for Selective Prodrug Activation and Chemotherapeutic Action in Cancers

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