Chemotherapy is one of the main treatments used to combat cancer. A great number of antitumor compounds are natural products or their derivatives, mainly produced by microorganisms. In particular, actinomycetes are the producers of a large number of natural products with different biological activities, including antitumor properties. These antitumor compounds belong to several structural classes such as anthracyclines, enediynes, indolocarbazoles, isoprenoides, macrolides, non-ribosomal peptides and others, and they exert antitumor activity by inducing apoptosis through DNA cleavage mediated by topoisomerase I or II inhibition, mitochondria permeabilization, inhibition of key enzymes involved in signal transduction like proteases, or cellular metabolism and in some cases by inhibiting tumor-induced angiogenesis. Marine organisms have attracted special attention in the last years for their ability to produce interesting pharmacological lead compounds.

Summary: S treptomyces albus J 1074 is a streptomycete strain widely used as a host for expression of secondary metabolite gene clusters. Bioinformatic analysis of the genome of this organism predicts the presence of 27 gene clusters for secondary metabolites. We have used three different strategies for the activation of some of these silent/cryptic gene clusters in S . albus J 1074: two hybrid polyketide‐non‐ribosomal peptides ( PK‐NRP ) (antimycin and 6‐ epi ‐alteramides), a type I PK (candicidin), a non‐ribosomal peptides ( NRP ) (indigoidine) and glycosylated compounds (paulomycins). By insertion of a strong and constitutive promoter in front of selected genes of two clusters, production of the blue pigment indigoidine and of two novel members of the polycyclic tetramate macrolactam family (6‐ epi ‐alteramides A and B ) was activated. Overexpression of positive regulatory genes from the same organism also activated the biosynthesis of 6‐ epi ‐alteramides and heterologous expression of the regulatory gene pim M of the pimaricin cluster activated the simultaneous production of candicidins and antimycins, suggesting some kind of cross‐regulation between both clusters. A cluster for glycosylated compounds (paulomycins) was also identified by comparison of the high‐performance liquid chromatography profiles of the wild‐type strain with that of a mutant in which two key enzymes of the cluster were simultaneously deleted.

Covering: 2002 to September 2009 In recent years, a number of gene clusters involved in the biosynthesis of polyketide compounds have been characterized and the genes have been used for designing and developing novel chemical entities by combinatorial biosynthesis. This review covers the highlights of combinatorial biosynthesis using polyketide-modifying enzymes such as oxidoreductases, group transferases, halogenases, cyclases and deoxysugar biosynthesis enzymes, focusing on those from actinomycetes (with 315 references cited).

Covering: up to October 2008 Antitumor compounds produced by actinomycetes and novel derivatives generated by combinatorial biosynthesis are reviewed (with 318 references cited). The different structural groups for which the relevant gene clusters have been isolated and characterized are reviewed, with a description of the strategies used for the generation of the novel derivatives and the activities of these compounds against tumor cell lines.