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APLIDINE treatment of cancers

A cancer, dose technology, applied in the direction of medical preparations containing active ingredients, depsipeptides, peptide/protein ingredients, etc., can solve the problems of ineffectiveness and limited treatment implementation.

Inactive Publication Date: 2003-06-11
PHARMA MAR U
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The same is true for patients who relapse after progressive disease previously treated with existing therapy, in which further similar therapy is often ineffective due to acquired drug resistance or because of associated toxicities that limit the availability of therapy

Method used

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  • APLIDINE treatment of cancers
  • APLIDINE treatment of cancers
  • APLIDINE treatment of cancers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Gene expression patterns of human leukemia MOLT4 cells treated with the marine compound aplidine

[0087] Early changes in gene expression induced by aplidine in MOLT-4 cells were assessed by using cDNA expression arrays (Atlas Human Cancer, Clontech). MOLT-4 cells were treated for 1 hour with aplidine at a concentration that inhibited growth by 50%, and total RNA was isolated at 0, 1, 6 and 24 hours after drug elution. The filters were hybridized with equal amounts of 32P-labeled cDNA. The results were analyzed with ATLAS IMAGE 1.0 software. A change in gene expression of more than twofold was considered a significant change in RNA expression and was subsequently confirmed by PCR. A significant time-dependent decrease in VEGF-R1 (flt-1) expression was observed and confirmed at the RNA and protein levels by PCR and Western blotting, respectively.

Embodiment 2

[0089] Correlation of the selective antitumor activity of the marine-derived compound aplidine obtained with different model systems

[0090] Different model systems are evaluated to provide a basis for further clinical work. Selective antitumor activity was observed against two histologically distinct solid tumors: human gastric and prostate carcinomas. Potent in vitro activity against primary gastric tumor specimens or Hs746T gastric tumor cells was evident with ICs of 146 and 450 pM, respectively 50 value performance. It is judged that the IC50 activity on PC-3 prostate tumor cells is 3.4nM, the potency is low, but the selectivity is not low. In vitro activity in nude rodents was assessed using sc implanted tumor fragments or hollow fibers (HF) containing tumor cells.

[0091] the tumor

[0092] Optimal activity was observed after intraperitoneal administration in xenografted gastric (17-20%) and prostate (25-38%) tumors. Follow-up studies require intravenous ...

Embodiment 3

[0094] A phase I and pharmacokinetic study of weekly 24-hour infusions of aplidine in patients with advanced solid tumors

[0095] In vivo studies found increased in vivo activity by prolonging the duration of infusion. Sixteen patients were treated in this study. Patient characteristics were: mean age 55 years, mean PS 1, 11 / 5 male / female, tumor types: 5 head and neck tumors, 2 renal tumors, 3 colon tumors, 2 rectal tumors, sarcoma 1 case, 3 cases of melanoma, all patients had undergone chemotherapy pretreatment (average 2 lines).

[0096] Aplidine was administered as a 24-hour infusion at the following dose levels (Dls): 133 (3pts), 266 (3pts), 532 (3pts), 1000 (3pts), 2000 (3pts) and 3000 (1pts) mcg / m 2 / wk×3.

[0097] No dose-limiting toxicities (DLTs) were observed. Only non-hematological toxicities consisting of Grade 1 nausea, Grade 1 mucositis, and Grade 1 fatigue were reported. Phlebitis in the infusion arm was common and concentration-dependent. Pharmacokinet...

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Abstract

Aplidine demonstrates considerable promise in phase (I) clinical trials for treatment of tumours, and various dosing regimes are given. Tumor reduction has been observed in several tumour types including renal carcinoma, colorectal cancer, lung carcinoid, medullary thyroid carcinomas and melanoma. It has also been found that aplidine has a role in inhibiting angiogenesis, complementing the anti-tumour activity.

Description

[0001] The present invention relates to the treatment of cancer. Background of the invention [0002] Cancer comprises a group of malignant neoplasms that can be divided into two categories, carcinomas, including most cases observed in the clinic, and other less common cancers, including leukemias, lymphomas, central nervous system tumors, and sarcomas. Carcinomas arise from epithelial tissue, while sarcomas arise from connective tissue and structures originating from mesodermal tissue. Sarcomas can affect, for example, muscle or bone, and occur in the bone, bladder, kidney, liver, lung, parotid gland, or spleen. [0003] Cancer is aggressive and easily metastasizes to new locations. It spreads directly to surrounding tissues and can also spread through the lymphatic and circulatory systems. There are many treatments for cancer, including surgery and radiation therapy for localized disease, as well as drugs. However, the efficacy of existing therapies for many cancer types ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K31/136A61K31/205A61K38/00A61K38/15A61K45/00A61P35/00
CPCA61K38/15A61K31/205A61P35/00A61K2300/00A61K38/00
Inventor G·T·费尔克洛思C·特韦维斯L·帕滋-阿雷斯
Owner PHARMA MAR U
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