Provided here is a comprehensive examination of the basic and clinical condition of three innovative and promising approaches to cancer therapy, which may support or even substitute chemotherapy: differentiation, immunomodulation, and inhibition of angiogenesis. Differentiation shouldnormalize neoplastic cells and make them compatible with the host. Its feasibility with retinoids, interferons, chemotherapeutic and other agents is discussed. Modulation by biological agents, cytotoxic effector cells and drugs is considered in attempts to boost endogenous antitumour defenses and/or to render neoplastic cells more susceptible to the immune attack of the host. Finally, the important aspect of interfering with tumour blood vessel development and function is taken into account. Consideringthe importance that chemotherapy has in cancer treatment and in view of a more and more integrated strategy, the relationship between the aforementioned approaches and chemotherapeutic agents and chemoresistance is treated in detail.

The addition of chemotherapy as an effective means to treat cancer has had a major impact on selected human malignancies. Due to a general inability to dif ferentiate between normal and neoplastic cells, little selectivity exists in currently used oncolytic drugs. Consequently, significant toxicity to the patient is expected when systemic cancer chemotherapy is chosen as an appropriate therapeutic in tervention. Much of this toxicity, such as damage to the bone marrow, gastroin testinal tract, or hair follicles, is predictable based upon the fact that anticancer drugs kill actively dividing cells. These types of toxicities, while serious, are usually manageable and reversible and are, therefore, not often considered to be dose limiting. Unfortunately, several of the most important anticancer drugs also damage tissues in which the growth fraction is relatively small. Such toxicities can not be predicted based on the chemical structure of the drugs, are often not detected in preclinical studies, and are encountered frequently for the first time in clinical studies. Further, unlike most of the proliferative-dependent toxicities, the unpre dicted toxicities are usually irreversible or only partially reversible upon cessation of drug administration. Because of this, the unpredicted toxicities are referred to as dose limiting. They represent a significant barrier to the ultimate efficacy of several of our most important anticancer drugs.

The addition of chemotherapy as an effective means to treat cancer has had a major impact on selected human malignancies. Due to a general inability to dif ferentiate between normal and neoplastic cells, little selectivity exists in currently used oncolytic drugs. Consequently, significant toxicity to the patient is expected when systemic cancer chemotherapy is chosen as an appropriate therapeutic in tervention. Much of this toxicity, such as damage to the bone marrow, gastroin testinal tract, or hair follicles, is predictable based upon the fact that anticancer drugs kill actively dividing cells. These types of toxicities, while serious, are usually manageable and reversible and are, therefore, not often considered to be dose limiting. Unfortunately, several of the most important anticancer drugs also damage tissues in which the growth fraction is relatively small. Such toxicities can not be predicted based on the chemical structure of the drugs, are often not detected in preclinical studies, and are encountered frequently for the first time in clinical studies. Further, unlike most of the proliferative-dependent toxicities, the unpre dicted toxicities are usually irreversible or only partially reversible upon cessation of drug administration. Because of this, the unpredicted toxicities are referred to as dose limiting. They represent a significant barrier to the ultimate efficacy of several of our most important anticancer drugs."