Current Cancer Therapy Reviews - Volume 2, Issue 3, 2006

Myelodysplastic syndrome (MDS) represents a group of malignant clonal disorders characterized by ineffective hematopoiesis and an accumulation of hematopoietic precursors in the bone marrow, frequently resulting in transformation to acute leukemia and death. However, recent understanding of MDS pathophysiology has provided novel treatment approaches with pharmacologic agents capable of manipulating pathways intrinsic and extrinsic to the malignant hematopoietic clone. These advances provide new therapeutic options for patients and provide a basis for further understanding and treatment of this disease.

Ovarian cancer is a leading cause of death from gynecological cancer. Although most patients will experience remission of their disease, following cytoreductive surgery and platinum (+ paclitaxel) chemotherapy, relapse will occur in about 80% of cases with FIGO stages III and IV disease. Treatment of recurrent ovarian cancer represents a challenge. Cure is rare but long-term survival can be achieved in a significant proportion of patients. Treatment-free interval after first-line platinum-based chemotherapy determines sensitivity to platinum rechallenge. Nevertheless, other factors, such as symptoms, tumor bulk, ECOG PS and patients' preferences can also aid decision making in this setting. The recent ICON4/AGO and GCIC studies showed that combination of carboplatin with paclitaxel or gemcitabine are superior to carboplatin monotherapy in patients with platinum-sensitive disease, but at the expense of additional toxicity. Platinum refractory disease is associated with poor prognosis and monotherapy with a non-platinum agent, such as liposomal doxorubicin, topotecan or a taxane is recommended. Biological agents targeting various components on cancer cells, such as vascular endothelial growth factor (VEGF), growth factors and stromal elements, are under investigation as adjuncts to chemotherapy. In addition, selected patients may benefit from surgery at recurrence, but they represent the minority of patients with relapsed ovarian cancer.

Our rapidly expanding understanding of the molecular pathogenesis of a variety of cancers is providing new molecular targets for drug development; specifically, immunomodulatory and antiangiogenic agents are poised to become essential in novel cancer therapeutics. Rationale for the development of such therapies rest in the observation that these immune and angiogenic targets (e.g. TNF-α , VEGF, IL-6, IL-2 and IFN-γ ) are at the core of cancer growth and progression, and are aberrant and deregulated in many human malignancies. Successful immunomodulation and inhibition of aberrant angiogenesis pathways are essential for malignant tumor cells. Herein we present an overview of immune modulation and angiogenesis in cancer. We will also review preclinical and clinical development, pharmacology and clinical trials of lenalidomide (Revlimid®, formerly CC-5013; Celgene Corporation), and agent that alters both pathways.

The tumor suppressor protein p53 plays an important role in maintaining genomic integrity. p53 possesses an intrinsic 3'→ 5' exonuclease activity. The presence of exonuclease activity has been implicated in the prevention of mutator phenotype and in acquired resistance to chemotherapeutic agents. p53 may act as proofreading exonuclease for DNA polymerases during DNA replication. The recombinant wild-type p53 can proofread for various exonuclease-deficient cellular and viral DNA polymerases. The preferential excision of mismatched nucleotides from DNA by 3'→5' exonuclease activity enhances the fidelity of DNA synthesis, thus providing a biochemical mechanism to reduce mutations caused by incorporation of mismatched nucleotides. P53 exonuclease activity for different mismatches is dependent upon the nature of the mispair. The observed specificity of mismatch excision indicates that p53 exonucleolytic proofreading preferentially repairs transversion mutations. Interestingly, p53 exonuclease activity preferentially removes the same base that is less efficiently incorporated and extended by the DNA polymerase. Hence, the proofreading activity of p53 may limit the transversion mutations, indicating that the mutation spectra might be affected by the actions of DNA polymerase and p53-exonuclease. p53 was found in the nucleus and in the cytoplasm of the cell. In cytoplasmic extracts, non-induced p53, displays high level of 3'→ 5' exonuclease activity in comparison to nuclear extracts. P53 may recognize and remove incorporated nucleoside analogs from DNA in vitro, in whole cells and in cytoplasm. These findings raise the possibility that resistance to anti-cancer and anti-viral nucleoside analogs, in part, may involve the excision of incorporated drug during DNA synthesis.

Sentinel lymph nodes (SLN) receive lymphatic drainage from the primary tumour and have been regarded as sensitive and reliable indicators of disease progression. It has been postulated that absence of metastatic tumour in SLN might obviate the exigency of axillary clearance and avoid the associated morbidity. But debate continues about the need for complete axillary dissection in SLN positive breast cancer patients, and whether SLN positivity might reflect the involvement of non-SLN. In essence, SLN positivity might be an invaluable aid in patient management. Albeit fraught with much debate, it would be worthwhile examining importance of the presence of micrometastases in patient management and disease outcome. Some of these considerations have led to the identification of molecular markers and measurement of their expression in SLN and non-SLN using sensitive, specific and precise molecular biological techniques. Several molecular markers of cancer progression have been employed in this way. These are related to the state of differentiation, and cell proliferation and apoptosis of tumours. Tumour suppressor genes and oncogenes have also been seen as ideal markers of SLN involvement. Significant advances have also been made in the elucidation of pathways of signalling that angiogenic and lymphangiogenic factors use and these have also contributed to the identification of potential markers of lymphangiogenesis. The availability of such a wide spectrum of markers requires not only that their expression is assessed objectively but also that potential difficulties of interpreting the complex interactions and inter-relationships between these markers and their bearing on disease progression and prognosis are addressed and assessed, which robustly advocates the use of artificial intelligence systems for this purpose. Construction of molecular profiles of primary tumours and disseminated tumour in SLN and body fluids would be invaluable for assessing cancer progression, for the prediction of prognosis and in designing therapeutic clinical trials.

Treatment of testicular germ cell tumors (TGCTs) has been a success primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy. Despite the promise of cure for the majority of TGCT patients, the effectiveness of therapy for some patients is limited by toxicity and the problem of resistance. There is compelling rationale to further understand the biology of TGCTs in order to better treat other solid tumors and to address the shortcomings of present TGCT therapies. TGCTs contain undifferentiated pluripotent stem cells, known as embryonal carcinoma, that share many properties with human embryonic stem cells. The importance of cancer stem cells in the initiation, progression and treatment of solid tumors is beginning to emerge. We discuss TGCTs in the context of solid tumor curability and targeted cancer stem cell therapy.

Bone marrow (BM) suppression is an important dose-limiting side effect of chemotherapy and radiotherapy for cancer. Although acute myelosuppression is an immediate concern for patients undergoing cancer therapy, its management has been improved significantly in recent years by the use of various hematopoietic growth factors. However, many patients receiving chemotherapy and/or ionizing radiation (IR) also develop residual (or long-term) BM injury (a sustained decrease in HSC reserves due to an impairment in HSC self-renewal) after the recovery from acute myelosuppression. Unlike acute myelosuppression, residual BM injury is latent and long lasting and shows little tendency for recovery. Following additional hematopoietic stress such as subsequent cycles of consolidation cancer treatment or autologous BM transplantation, residual BM injury can deteriorate to become a hypoplastic or myelodysplastic syndrome. This article review some of the new developments in elucidating the cellular and molecular mechanisms whereby chemotherapy and radiotherapy cause residual BM injury. Particularly, we discuss the role of induction of hematopoietic stem cell (HSC) senescence via the p53-p21Cip1/Waf1 and/or p16Ink4a-RB pathways in the induction of the injury and the therapeutic potential of molecularly targeting these pathways for amelioration of chemotherapy- and radiotherapy-induced long-term BM toxicity.