A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors.

PURPOSE: Expression of the Bcl-2 protein confers resistance to various apoptotic signals. G3139 [oblimersen sodium (Genasense)] is a phosphorothioate antisense oligodeoxynucleotide that targets Bcl-2 mRNA, downregulates Bcl-2 protein translation, and enhances the antitumor effects of subtherapeutic doses of docetaxel (Taxotere). PATIENTS AND METHODS: We performed a phase I trial to determine the maximum tolerated dose (MTD) and safety profile of combined therapy with G3139 and weekly docetaxel in patients with advanced Bcl-2-positive solid tumors. Cohorts of three to six patients were enrolled to escalating doses of G3139 and a fixed dose of weekly docetaxel using either of two schedules. In part I, G3139 was administered by continuous infusion for 21 days (D1-22), and docetaxel (35 mg/m2) was given weekly on days 8, 15 and 22. In part II, G3139 was given by continuous infusion for 5 days before the first weekly dose of docetaxel, and for 48 h before the second and third weekly docetaxel doses. For both schedules, cycles were repeated every 4 weeks. RESULTS: Twenty-two patients were enrolled. Thirteen patients were treated on the part I schedule with doses of G3139 escalated from 1 to 4 mg/kg/day. Nine patients were on the part II schedule of shorter G3139 infusion at G3139 doses of 5-9 mg/kg/day. Hematologic toxicities were mild, except for one case of persistent grade 3 thrombocytopenia in part I. The most common adverse events were cumulative fatigue and transaminase elevation, which prevented further dose escalation beyond 4 mg/kg/day for 21 days with the part I schedule. In part II of the study, using the abbreviated G3139 schedule, even the highest daily doses were tolerated without dose-limiting toxicity or the need for dose modification. Objective tumor response was observed in two patients with breast cancer, including one whose cancer previously progressed on trastuzumab plus paclitaxel. Four patients had stable disease. Pharmacokinetic results for G3139 were similar to those of other trials. CONCLUSIONS: G3139 in combination with standard-dose weekly docetaxel was well tolerated. The shortened and intermittent G3139 infusion had less cumulative toxicities and still allowed similar total G3139 delivery as the longer infusion. Further studies should examine the molecular effect of the regimen, as well as clinical activities in malignancies for which taxanes are indicated.

Molecular and pharmacological aspects of antiestrogen resistance.

Endocrine therapy is effective in approximately one-third of all breast cancers and up to 80% of tumors that express both estrogen and progesterone receptors. Despite the low toxicity, good overall response rates, and additional benefits associated with its partial agonist activity, most Tamoxifen-responsive breast cancers acquire resistance. The development of new antiestrogens, both steroidal and non-steroidal, provides the opportunity for the development of non-cross-resistant therapies and the identification of additional mechanisms of action and resistance. Drug-specific pharmacologic mechanisms may confer a resistance phenotype, reflecting the complexities of both tumor biology/pharmacology and the molecular endocrinology of steroid hormone action. However, since all antiestrogens will be effective only in cells that express estrogen receptors (ER), many mechanisms will likely be directly related to ER expression and signaling. For example, loss of ER expression/function is likely to confer a cross-resistance phenotype across all structural classes of antiestrogens. Altered expression of ERalpha and ERbeta, and/or signaling from transcription complexes driven by these receptors, may produce drug-specific resistance phenotypes. We have begun to study the possible changes in gene expression that may occur as cells acquire resistance to steroidal and non-steroidal antiestrogens. Our preliminary studies implicate the altered expression of several estrogen-regulated genes. However, resistance to antiestrogens is likely to be a multigene phenomenon, involving a network of interrelated signaling pathways. The way in which this network is adapted by cells may vary among tumors, consistent with the existence of a highly plastic and adaptable genotype within breast cancer cells.

Maternal and prepubertal diet, mammary development and breast cancer risk.

At present, we do not know what causes sporadic breast cancer. Environmental factors,particularly diet, appear to explain at least 70% of newly diagnosed breast cancers, but it is not clear what these factors are. We propose that the lack of progress in this area is due to a lack of considering the effect of timing of environmental and dietary exposures on the breast. The evidence provided above suggests that an in utero exposure to an estrogenic environment-including that caused by diet [high (n-6) PUFA or genistein]-increases breast cancer risk. This increase may be mediated by an increased presence of TEB in the mammary epithelial tree and increased ER-alpha levels, reduced ER-beta levels or both. Prepubertal estrogenic exposure, in contrast, reduces later risk of developing breast cancer. The protective effect of estrogens may be mediated by early epithelial differentiation, reduced presence of ER-alpha and increased levels of ER-beta in the mammary gland. The challenge we are now facing is to determine whether the data obtained mainly through the use of animal models is relevant to women and if so, how we might be able to modulate pregnancy and childhood estrogenic exposure by appropriate dietary modifications to reduce breast cancer risk in women.

Does p53 status influence tumor response to anticancer therapies?

Abnormalities in the tumor suppressor gene p53 have been identified in over 60% of human cancers. Since it plays such a pivotal role in cell growth regulation and apoptosis, the status of the p53 gene has been proposed as one of the major determinants of a tumor's response to anticancer therapies. In this review we examine the relationship between functional p53 and sensitivity/resistance to both chemotherapy and radiotherapy, and discuss the potential use of some of the current gene therapy approaches to restore functional p53 to tumors as a means of modulating the effects of radiation and chemotherapy.

Genistein: does it prevent or promote breast cancer?

Diet is estimated to contribute to approximately 50% of all newly diagnosed breast cancers. As such, a search for dietary factors differentially consumed among populations with increased breast cancer risk (e.g., Caucasians) compared to those with low risk (e.g., Asians) has become a priority. One such dietary component, which is typical to the Asian but not the Caucasian diet, is soy. We review data relevant to attempts to determine whether soy, and more specifically genistein, is a dietary component that may help to explain the dramatic disparity in breast cancer risk among these populations.

Tp53 gene therapy: a key to modulating resistance to anticancer therapies?

Abnormalities in the p53 tumor suppressor have been identified in over 60% of human cancers. The status of p53 within tumor cells has been proposed to be one of the major determinants of the response to anticancer therapies. In this review we examine the relationship between functional p53 and sensitivity, or resistance, to chemotherapy and radiotherapy. We also discuss the potential of current gene-therapy approaches to restore functional p53 to tumors as a means of modulating the effects of radiation and chemotherapy.