New approaching to Cancer Therapy & Diagnosis
le Coutre P, Mologni L, Cleris L, et al [Istituto Nazionale Tumori, Milan, Italy; Novartis Internatl Inc, Basel, Switzerland]
In Vivo Eradication of Human BCR/ABL Positive Leukemia Cells with an ABL Kinase Inhibitor
J Natl Cancer Inst 91: 163-168, 1999
Chronic myeloid leukemia is caused by reciprocal chromosomal translocation [ Philadelphia chromosome] in hematopoietic stem cells. The Bcr/Abl fusion protein resulting from this translocation has enhanced tyrosine kinase activity. This study of nude mice human leukemia cells mice [ BCR/ABL -Positive] when given CGP57148B a potent BCR/ABL kinase inhibitor could block the BCR/ABL protein and curves were observed in 87% to 100% of treated mice when this compound was administered over an 11 day period.
Gerald Shklar, and Se-Kyung Oh (Division of Oral Pathology, Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Boston, Massachusetts)
Experimental Basis for Cancer Prevention by Vitamin E
Cancer Investigation 2000 Vol. 18 (3) Pg. 214-222
Recent clinical trials have demonstrated significant cancer preventive potential of vitamin E. Experimental cancer model such as hamster buccal pouch which closely resembles its human counterpart have shown significant inhibition of carcinogenesis with systemic administration of vitamin E.
In addition the other properties documented were its well known antioxidant properties, immunoenhancer, activator of p53 tumor supressor gene and an inhibitor of tumor angiogenesis.
Animal studies are now being confirmed in humans. The low levels of vitamin E in serum and plasma were found to be associated with an increased risk of lung and cervical cancer and prostate cancer mortality. Vitamin E has been shown to reduce the toxicity of adriamycin and enhance the anticancer effect of melphalan.
Leanne Cartee, Gregory L. Kucera (Department of Hematology/Oncology Medical College of Virginia, Richmond, Virginia, et al)
Protein Kinase C Modulation and Anticancer Drug Response
Cancer Investigation 2001 Vol. 18 (8) Pg. 731-739
Apoptosis, active form of cell death occurs in response to any circumstances including due to cancer chemotherapy. Intracellular signal transduction pathways are instrumental for many events in the cell including apoptosis.
Protein kinase C (PKC) transducers signal linked to diverse cellular processes including growth, differentiation, proliferation, platelet activation, tumor promotion and secretion.
Manipulating PKC to favor apoptosis in cancer well would hence improve therapies for cancer. In vitro studies have revealed improved gemcitabine and cytarabine cytotoxicity by manipulation of PKC signal transduction pathway. PKC signaling influences both the G0/G1 and G2 phases of cell cycle checkpoints.
Bryostatin 1 is a PKC activator and has been found to enhance the cytotoxicity of chemotherapeutic agent.
PKC inhibitors such as Staurosporine analogues UCN-01 and Calphostin C have cytotoxic effects in vitro studies.
Tarun Wasil, and Aby Buchbinder (North Shore University Hospital, New York University School of Medicine, Manhasset, New York)
Gene Therapy in Human Cancer: Report of Human Clinical Trials
Cancer Investigation 2001 Vol. 18 (8) Pg. 740-746
Gene therapy is a technique whereby genetic material is introduced into cells to correct a genetic defect or to alter the properties of a cell, thereby giving a therapeutic benefit to the recipient.
The transfer of genetic material can be performed ex vivo i.e. by manipulating cells outside of the body and reintroducing the modified cells in patient or by directly introducing the genetic material in the patient.
The genetic material introduction requires to be packed into a viral vector such as those derived from amphotropic retroviruses and adenoviruses, liposomes and naked DNA.
The studies carried out in humans on gene therapy have been to determine the safety of various approaches using gene therapy. The expression of wild type p53 in tumour using a adenoviral vector have been tried in head and neck cancer, colon cancer, metastatic to the liver, melanomas and non small cell lung cancers with marginal clinical benefit.
Induction of an antitumor immune response by incorporation of IL-12, IL-2 and granulocyte macrophage CSF gene has also been tried in patients in melanoma and various other solid tumors.
The EIA tumour suppressor gene that down regulates Her-2/neu oncogene have been tried in breast or head and neck cancer. The other familiar approach in gene therapy is making tumors sensitive to gancyclovir by introducing HSV-Tk gene, herpes simplex thymidine kinase gene which is necessary to activate gancyclovir, a prodrug, into an active antineoplastic drug. This approach has been tried in metastatic brain tumor and malignant mesotheliomas.
The MDR-1 gene responsible for resistance to chemotherapeutic agents have been packaged in a retroviral vector and introduced in CD 34+ hematopoietic agent precursors to induce resistance of their normal cells to chemotherapeutic agents and these were introduced in the setting of peripheral blood transplantation after high dose chemotherapy.
Nancy L. Lewis, and Neal J. Meropol (Divisions of Medical Science and Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania)
Oral Fluoropyrimidines in Cancer Treatment
Cancer Investigation 2001 Vol. 18 (8) Pg. 747-760
The development of oral fluoropyrimidines have the added advantage of ease of administration and patients preference. The predominant mechanism for intracellular cytotoxic effect of 5-FU, inhibition of thymidylate synthase (TS), incorporation into RNA, and incorporation into DNA.
Protected exposure of 5-FU improves the efficacy and decreases toxicity compare with bolus schedules in patients with colorectal cancer.
These oral fluoropyrimidines have been useful due to these protected daily administrative schedules. Capecitabine (Xeloda) a fluoropyrimidine carbamate is ultimately converted in vivo to 5-FU. When given in intermittent dosing schedule diarrhea, palmar-plantar erythrodysesthesia is a common problem.
The U.S. Food and Drug administration has approved capecitabine use in patients with refractory breast cancer. It has shown comparable toxicity with intravenous 5-FU/calcium leucovorin.
UFT is a fixed combination of tegafur (ftorafur) plus uracil in a 1:4 molar concentration. Uracil is a natural pyrimidine, serves to competitively inhibit 5-FU degradation by DPD and tegafur is a 5-FU prodrug absorbed as an intact molecule and gradually converted to 5-FU by P450 liver enzymes and TP.
It was found to be inactive in patients of colorectal cancer failed with 5-Fluorouracil. Japanese study have revealed improved 5-year survival rates when UFT is given with mitomycin. UFT when combined with cisplatinum had good response rates, 94% in previously untreated head and neck cancer patients UFT has activity in breast cancer patients. An overall response rate of 31% for metastatic breast cancer.
Eniluracil, a uracil analogue, is a potent irreversible inactivator of DPD. Eniluracil renders 5-FU 100% bioavailable and the half life of 5-FU is increased from 15 minutes to 5 hours. Eniluracil has activity in colorectal cancer. The combination of oral 5-FU, eniluracil and radiation therapy for head and neck cancer did show activity with major toxicities. It has also shown some activity in hepatocellular.
S-1 is a combination of tegafur, CDHP and oxonic acid is a fixed molar ratio of 1:0.4:1. It has shown significant activity in previously treated patients with gastric cancer, 40% approximately.
The future direction would be to study biochemical composition of the tumour and then plan the therapy. Tumors with high TP (thymidine phosphorylase) would be treated with capecitabine whereas those with high dihydropyrimidine dehydrogenase would be best treated with eniluracil / 5-FU.
Lucas R, Holmgren L, Garcia I, et al (Geneva Univ Hosp; Karolinska Inst, Stockholm; Univ Med Ctr, Geneva; et al)
Multiple Forms of Angiostatin Induce Apoptosis in Endothelial Cells
Blood 92: 4730-4741, 1998
Angiogenesis is vital for tumor growth and hence pharmacologic inhibition of angiogenesis is an important therapeutic intervention. Angiostatin a proteolytic cleavage product of plasminogen is a potent inhibitor of angiogenesis.
The investigators have studied the effect of angiostatin on endothelial cells and interestingly its antiangiogenic effect was shown by inducing apoptosis of the endothelial cells.
This could be one of its mechanism of action through deregulation of integrins on the surface of endothelial cells.
Salven P, Orpana A, Joensuu H, (Helsinki Univ)
Leukocytes and Platelets of Patients With Cancer Contain High Levels of Vascular Endothelial Growth Factor
Clin Cancer Res 5: 487-491, 1999
Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen and permeability factor.
This study of 52 patients with cancer and 50 healthy control subjects underwent peripheral venous blood collection and measurement of VEGF in serum, blood, whole blood and peripheral blood mononuclear cells.
In the lysed whole blood samples the blood VEGF (B-VEGF) were higher in patients with cancer than in control and high B-VEGF were associated with high leukocyte count in healthy individual but not with high platelet counts and the levels of B-VEGF was higher in patients with cancer than control subjects with similar leukocyte and platelet count.
Thus VEGF transported in blood stream by blood cells and blood cells of patients with cancer contain high concentration of VEGF which is an angiogenic growth factor. The measured level of VEGF in serum may be falsely low in some patients and adjustment for platelet level as well as consideration to measured level in plasma should be considered.
Aoki Y, Tosato G (Food and Drug Administration, Bethesda, Md)
Role of Vascular Endothelial Growth Factor/Vascular Permeability Factor in the Pathogenesis of Kaposis Sarcoma-Associated Herpesvirus-Infected Primary Effusion Lymphomas
Blood 94: 4247-4254, 1999
Kaposi sarcoma-associated herpesvirus (KSHV) is known as etiologic agent for the development of Kaposi sarcoma, primary effusion lymphoma and in some patients, Castleman disease.
Malignant lymphomatous effusions in body cavity are presenting features of primary effusion lymphomas. Primary effusion cell lines BC-1, BCP-1, and BCBL-1 were used and these produced high levels of VEGF/VPF.
This preclinical study demonstrated that VEGF may be significant factors due to its effect on permeability in development of effusion.
Gorski DH, Mauceri HJ, et al (Univ of Chicago; Northwestern Univ, Chicago; Beth Israel Deaconess Med Ctr, Boston; et al)
Potentiation of the Antitumor Effect of Ionizing Radiation by Brief Concomitant Exposures to Angiostatin
Cancer Res 58: 5686-5689, 1998
Angiostatin suppresses angiogenesis, thereby prevents tumor growth and metastasis.
This preclinical study of angiostatin was used in conjunction with ionizing radiation in halting the growth of Lewis lung carcinoma growing in hind limbs of syngeneic mice.
There had been a concern over the possibility of antiangiogenic therapy bringing about hypoxia and thereby having counter activity for radiation. But in this preclinical study the combination of angiostatin and radiation enhanced the anti tumor activity
Yoshida H, for the IHIT Study Group (Univ of Tokyo; et al)
Interferon Therapy Reduces the Risk for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C in Japan
Ann Intern Med 131: 174-181, 1999
This study of 2400 patients with chronic hepatitis C from Japan who had received interferon were assessed for fibrosis, virologic, and biochemical response and screened for hepatocellular carcinoma.
The annual incidence of hepatocellular cancer among untreated patients increased with the degree of liver fibrosis. Interferon could reduce the development of hepatocellular carcinoma and especially in those patients with sustained virologic and biochemical response.
Bieligk SC, Ghossein R, et al (Univ of Texas Southwestern Med Ctr, Dallas; Mem Sloan-Kettering Cancer Ctr, New York)
Detection of Tyrosinase mRNA by Reverse Transcription-Polymerase Chain Reaction in Melanoma Sentinel Nodes
Ann Surg Oncol 6: 232-240, 1999
This study of 45 sentinel lymph node (SLN) from 28 patients with primary cutaneous malignant melanoma were analyzed for detection of tyrosinase mRNA by RT-PCR, as opposed to immunohistochemical or standard hematoxylin/eosin staining.
This method was highly sensitive, it detected all patients with morphologically positive disease but also had a reasonable rate of false-positive evaluations.
Cher ML, de Oliveira JG, et al (Wayne State Univ, Detroit; Barbara Ann Karmanos Cancer Inst, Detroit)
Cellular Proliferation and Prevalence of Micrometastatic Cells in the Bone Marrow of Patients With Clinically Localized Prostate Cancer
Clin Cancer Res 5: 2421-2425, 1999
This study of 46 patients with clinically localized prostate cancer underwent bone marrow analysis for messenger RNA for PSA. The samples were immunostained (cytokeratin) to determine the micrometastasis in bone marrow (BM) mononuclear cell and to characterize their proliferative status.
The prevalence of micrometastatic cells in BM varies widely among patients with clinically localized prostate cancer. The proportion of these cells in the proliferative phase also varies greatly. Androgen ablation decreases the number of micrometastatic cells.
The long-term follow-up of such patients would give information if recurrence is associated with proliferative status of micrometastatic cells.